bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2020‒07‒12
fifty-three papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. Trends Immunol. 2020 Jul 06. pii: S1471-4906(20)30127-7. [Epub ahead of print]
      It has become increasingly clear that the terms used to define memory T cell subsets no longer accurately reflect our understanding of memory T cell biology. Here, we discuss the limitations of our current terminology and propose a new approach for defining memory T cell subsets.
  2. PLoS One. 2020 ;15(7): e0235706
      During type 1 immune responses, CD4 T helper 1 (Th1) cells and CD8 T cells are activated via IL-12 and contribute to the elimination of intracellular pathogens through interferon gamma (IFNγ) production. In this study, we identified Placenta-specific 8 (Plac8) as a gene that is uniquely expressed in Th1 CD4 T cells relative to other CD4 T cell subsets and hypothesized that Plac8 may represent a novel therapeutic target in Th1 CD4 T cells. First, we determined that Plac8 mRNA in CD4 T cells was induced following IL-12 stimulation via an indirect route that required new protein synthesis. Upon evaluating the functional relevance of Plac8 expression in Th1 CD4 T cells, we discovered that Plac8 was important for suppressing IFNγ mRNA and protein production by CD4 T cells 24 hours after IL-12 stimulation, however Plac8 did not contribute to pathogenic CD4 T cell function during two models of intestinal inflammation. We also noted relatively high basal expression of Plac8 in CD8 T cells which could be further induced following IL-12 stimulation in CD8 T cells. Furthermore, Plac8 expression was important for establishing an optimal CD8 T cell response against influenza A virus via a T cell-intrinsic manner. Altogether, these results implicate Plac8 as a potential regulator of Th1 CD4 and CD8 T cell responses during Th1 T cell-driven inflammation.
  3. Immunometabolism. 2020 ;pii: e200020. [Epub ahead of print]2(3):
      Immune checkpoint therapies aiming to enhance T cell responses have revolutionized cancer immunotherapy. However, although a small fraction of patients develops durable anti-tumor responses, the majority of patients display only transient responses, underlying the need for finding auxiliary approaches. Tumor microenvironment poses a major metabolic barrier to efficient anti-tumor T cell activity. As it is now well accepted that metabolism regulates T cell fate and function, harnessing metabolism may be a new strategy to potentiate T cell-based immunotherapies.
    Keywords:  ROS; T cell differentiation; T cell memory; adoptive cell therapy; cancer immunotherapy; glycolysis; immunometabolism; mitochondria
  4. Trends Immunol. 2020 Jul 02. pii: S1471-4906(20)30132-0. [Epub ahead of print]
      The full potential of T cell-based immunotherapies remains limited by a variety of T cell extrinsic and intrinsic immunosuppressive mechanisms that can become imprinted to stably reduce the antitumor ability of T cells. Here, we discuss recent insights into memory CD8+ T cell differentiation and exhaustion and the association of these differentiation states with clinical outcomes during immune checkpoint blockade and chimeric antigen receptor (CAR) T cell therapeutic modalities. We consider the barriers limiting immunotherapy with a focus on epigenetic regulation impeding efficacy of adoptively transferred T cells and other approaches that augment T cell responses such as immune checkpoint blockade. Furthermore, we outline conceptual and technical breakthroughs that can be applied to existing therapeutic approaches and to the development of novel cutting-edge strategies.
    Keywords:  CAR T cells; T cell exhaustion; cancer immunotherapy; epigenetics; immune checkpoint blockade
  5. Eur J Immunol. 2020 Jul 06.
    Keywords:  CD4 T cells ⋅ CD 8 T cells ⋅ anti-CD3ε antibody ⋅ T cell activation ⋅ T cell memory formation
  6. Cardiovasc Res. 2020 Jul 09. pii: cvaa202. [Epub ahead of print]
      AIMS: Inflammation has important roles in atherosclerosis. CD4+CD28null (CD28null) T cells are a specialised T lymphocyte subset that produce inflammatory cytokines and cytotoxic molecules. CD28null T cells expand preferentially in patients with acute coronary syndrome (ACS) rather than stable angina and are barely detectable in healthy subjects. Importantly, ACS patients with CD28null T cell expansion have increased risk for recurrent acute coronary events and poor prognosis, compared to ACS patients in whom this cell subset does not expand. The mechanisms regulating CD28null T cell expansion in ACS remain elusive. We therefore investigated the role of cytokines in CD28null T cell expansion in ACS.METHODS AND RESULTS: High-purity sorted CD4+ T cells from ACS patients were treated with a panel of cytokines (TNF-α, IL-1β, IL-6, IL-7, IL-15), and effects on the number, phenotype and function of CD28null T cells were analysed and compared to the control counterpart CD28+ T cell subset. IL-7 and IL-15 induced expansion of CD28null T cells from ACS patients, while inflammatory cytokines TNF-α, IL-1β and IL-6 did not. The mechanisms underlying CD28null T cell expansion by IL-7/IL-15 were preferential activation and proliferation of CD28null T cells compared to control CD28+ T cells. Additionally, IL-7/IL-15 markedly augmented CD28null T cell cytotoxic function and interferon-γ production. Further mechanistic analyses revealed differences in baseline expression of component chains of IL-7/IL-15 receptors (CD127 and CD122) and increased baseline STAT5 phosphorylation in CD28null T cells from ACS patients compared to the control CD28+ T cell subset. Notably, we demonstrate that CD28null T cell expansion was significantly inhibited by Tofacitinib, a selective JAK1/JAK3 inhibitor that blocks IL-7/IL-15 signalling.
    CONCLUSIONS: Our novel data show that IL-7 and IL-15 drive the expansion and function of CD28null T cells from ACS patients suggesting that IL-7/IL-15 blockade may prevent expansion of these cells and improve patient outcomes.
    TRANSLATIONAL PERSPECTIVE: CD28null T cells expansion in ACS patients is an independent predictor of future acute coronary events and poor prognosis. The precise mechanisms underlying CD28null T cell expansion in ACS remain elusive. We show that IL-7 and IL-15 cytokines cause expansion of CD28null T cells from ACS patients by triggering activation and proliferation, and augment the cytotoxic function of these cells and production of inflammatory cytokines. We demonstrate that CD28null T cell expansion is inhibited by Tofacitinib that specifically blocks IL-7/IL-15 signalling. Further dissection of the roles of IL-7/IL-15 may lead to more effective and specific anti-inflammatory therapies in ACS.
  7. J Immunol. 2020 Jul 08. pii: ji2000137. [Epub ahead of print]
      Metabolic reprogramming plays a central role in T cell activation and differentiation, and the inhibition of key metabolic pathways in activated T cells represents a logical approach for the development of new therapeutic agents for treating autoimmune diseases. The widely prescribed antidiabetic drug metformin and the glycolytic inhibitor 2-deoxyglucose (2-DG) have been used to study the inhibition of oxidative phosphorylation and glycolysis, respectively, in murine immune cells. Published studies have demonstrated that combination treatment with metformin and 2-DG was efficacious in dampening mouse T cell activation-induced effector processes, relative to treatments with either metformin or 2-DG alone. In this study, we report that metformin + 2-DG treatment more potently suppressed IFN-γ production and cell proliferation in activated primary human CD4+ T cells than either metformin or 2-DG treatment alone. The effects of metformin + 2-DG on human T cells were accompanied by significant remodeling of activation-induced metabolic transcriptional programs, in part because of suppression of key transcriptional regulators MYC and HIF-1A. Accordingly, metformin + 2-DG treatment significantly suppressed MYC-dependent metabolic genes and processes, but this effect was found to be independent of mTORC1 signaling. These findings reveal significant insights into the effects of metabolic inhibition by metformin + 2-DG treatment on primary human T cells and provide a basis for future work aimed at developing new combination therapy regimens that target multiple pathways within the metabolic networks of activated human T cells.
  8. Nat Methods. 2020 Jul 06.
      T cells respond to threats in an antigen-specific manner using T cell receptors (TCRs) that recognize short peptide antigens presented on major histocompatibility complex (MHC) proteins. The TCR-peptide-MHC interaction mediated between a T cell and its target cell dictates its function and thereby influences its role in disease. A lack of approaches for antigen discovery has limited the fundamental understanding of the antigenic landscape of the overall T cell response. Recent advances in high-throughput sequencing, mass cytometry, microfluidics and computational biology have led to a surge in approaches to address the challenge of T cell antigen discovery. Here, we summarize the scope of this challenge, discuss in depth the recent exciting work and highlight the outstanding questions and remaining technical hurdles in this field.
  9. EMBO J. 2020 Jul 09. e104730
      The chimeric antigen receptor (CAR) directs T cells to target and kill specific cancer cells. Despite the success of CAR T therapy in clinics, the intracellular signaling pathways that lead to CAR T cell activation remain unclear. Using CD19 CAR as a model, we report that, similar to the endogenous T cell receptor (TCR), antigen engagement triggers the formation of CAR microclusters that transduce downstream signaling. However, CAR microclusters do not coalesce into a stable central supramolecular activation cluster (cSMAC). Moreover, LAT, an essential scaffold protein for TCR signaling, is not required for microcluster formation, immunological synapse formation, nor actin remodeling following CAR activation. However, CAR T cells still require LAT for an optimal production of the cytokine IL-2. Together, these data show that CAR T cells can bypass LAT for a subset of downstream signaling outputs, thus revealing a rewired signaling pathway as compared to native T cells.
    Keywords:   CAR ; LAT ; T cell signaling; actin; immunological synapse
  10. Clin Cancer Res. 2020 Jul 06. pii: clincanres.0558.2020. [Epub ahead of print]
      PURPOSE: T cell Ig and ITIM domain (TIGIT), a member of the immune checkpoint family, is important in normal T-cell biology. However, the phenotypical profile and clinical relevance of TIGIT in follicular lymphoma (FL) is largely unknown.EXPERIMENTAL DESIGN: Biopsy specimens from a cohort of 82 FL patients were analyzed using mass cytometry (CyTOF) to explore the phenotype and biological and clinical significance of TIGIT+ T cells.
    RESULTS: TIGIT is highly expressed on intratumoral T cells and its expression alters T cell phenotype in FL. TIGIT is abundantly expressed on Treg cells, resulting in an enhanced suppressive property. TIGIT expression on non-Treg/TFH T cells defines a population that exhibits an exhausted phenotype. Clinically, increased numbers of TIGIT+ T cells are associated with inferior patient outcomes and poor survival. We observe that anti-PD-1 therapy with pembrolizumab alters the phenotype of TIGIT+ T subsets and identifies a role for CD28 expression on TIGIT+ T cells in treatment response.
    CONCLUSION: The present study provides a comprehensive analysis of the phenotypic profile of intratumoral TIGIT+ T subsets and their prognostic relevance in FL. Inhibition of TIGIT signaling may be an additional mechanism to prevent T-cell suppression and exhaustion in B-cell lymphoma.
  11. Trends Cell Biol. 2020 Jul 02. pii: S0962-8924(20)30121-5. [Epub ahead of print]
      Effector CD8+ T cells are typically thought to be a homogenous group of cytotoxic cells that produce interferon-(IFN) γ. However, recent findings have challenged this notion because multiple subsets of CD8+ T cells have been described, each with distinct effector functions and cytotoxic potential. These subsets, referred to as the Tc subsets, have also been detected in tumor microenvironments (TMEs), where they potentially influence the antitumor response and patient outcomes. In this review, we highlight the prevalence and roles of Tc subsets in the TME. We also discuss their therapeutic applications in the context of adoptive immunotherapy to treat cancer.
    Keywords:  CD8(+) T cell; Tc subset; cytokines; immunotherapy
  12. J Virol. 2020 Jul 08. pii: JVI.00795-20. [Epub ahead of print]
      Checkpoint inhibitors are effective in restoring exhausted CD8+ T cell responses in persistent viral infections or tumors. Several compounds are in clinical use for different malignancies but also trials in patients with chronic viral infections were conducted. In the mouse model of persistent lymphocytic choriomeningitis virus (LCMV) infection, it was shown that checkpoint inhibitor treatment increased T cell proliferation and functionality but its influence on the antigen-specific T cell receptor (TCR) repertoire is unknown.NP396-specific CD8+ T cells dominate during acute LCMV infection and are predominantly exhausted during chronic infection. Next generation sequencing of NP396-specific TCRs showed that exhaustion corresponds with a significantly reduced NP396-specific TCR repertoire diversity: Shannon Index of 4 in immunized to 2.6 in persistently infected mice. Anti-PD-L1 treatment during persistent LCMV infection restored NP396-specific T cell responses and reduced viral titers. Nevertheless, "αPD-L1-treated" mice showed an even more narrowed TCR repertoire, with reduced TCR diversity compared to persistently infected control mice (Shannon Index of 2.1 and 2.6, respectively). Interestingly, αPD-L1 treatment induced narrowing of the TCR repertoire negatively correlates with functional and physical restoration of the antigen-specific T cell response. Further, we found that private, hyper-expanded TCR clonotypes dominated the T cell response after αPD-L1 treatment. Although being private, these top clonotypes from "αPD-L1-treated" mice revealed a more "closely-related" CDR3 motif pattern, compared to top clonotypes from persistently infected control mice. In conclusion, although targeting the PD-1/PD-L1 pathway re-invigorates exhausted CD8+ T cells, it fails to restore T-cell repertoire diversity.IMPORTANCE Checkpoint inhibitors are effective immunotherapeutics to restore cancer- and virus-induced exhausted CD8+ T cells, by enhancing the quality and survival of immune responses. Although checkpoint inhibitors are already used as therapy against various cancers, not much is known about their multifaceted impact on the exhausted CD8+ T cell receptor (TCR) repertoire. This study describes for the first time the evolvement of an exhausted antigen-specific CD8+ TCR repertoire under checkpoint inhibitor treatment. By using a well-established virus model, we were able to show major shifts towards oligoclonality of the CD8+ TCR repertoire response against a massively exhausted lymphocytic choriomeningitis virus (LCMV) epitope. While supporting viral control in the LCMV model, oligoclonality and more private of TCR repertoires may impact future pathogenic challenges and may promote viral escape. Our results may explain the ongoing problems of viral escapes, unpredictable autoimmunity and heterogeneous responses appearing as adverse effects of checkpoint inhibitor treatments.
  13. Mol Cell. 2020 Jul 02. pii: S1097-2765(20)30430-5. [Epub ahead of print]
      The inactive X chromosome (Xi) is inherently susceptible to genomic aberrations. Replication stress (RS) has been proposed as an underlying cause, but the mechanisms that protect from Xi instability remain unknown. Here, we show that macroH2A1.2, an RS-protective histone variant enriched on the Xi, is required for Xi integrity and female survival. Mechanistically, macroH2A1.2 counteracts its structurally distinct and equally Xi-enriched alternative splice variant, macroH2A1.1. Comparative proteomics identified a role for macroH2A1.1 in alternative end joining (alt-EJ), which accounts for Xi anaphase defects in the absence of macroH2A1.2. Genomic instability was rescued by simultaneous depletion of macroH2A1.1 or alt-EJ factors, and mice deficient for both macroH2A1 variants harbor no overt female defects. Notably, macroH2A1 splice variant imbalance affected alt-EJ capacity also in tumor cells. Together, these findings identify macroH2A1 splicing as a modulator of genome maintenance that ensures Xi integrity and may, more broadly, predict DNA repair outcome in malignant cells.
    Keywords:  X chromosome; alternative end-joining; alternative splicing; female viability; genome instability; macro-histone; macroH2A1
  14. Int Immunol. 2020 Jul 05. pii: dxaa046. [Epub ahead of print]
      Energy metabolism plays an important role in proliferating cells. Recent reports indicate that metabolic regulation or metabolic products can control immune cell differentiation, fate and reactions. Cancer immunotherapy based on blockade of programmed cell death protein 1 (PD-1) has been used worldwide, but a significant fraction of patients remain unresponsive. Therefore, clarifying the mechanisms and overcoming patient unresponsiveness are urgent issues. Because cancer immunity consists of interactions between the cancer and host immune cells, there has recently been a focus on the metabolic interactions and/or competition between the tumor and the immune system to address the issue of the unresponsiveness of some patients. Cancer cells render their microenvironment immunosuppressive, driving T cell dysfunction or exhaustion, which is advantageous for cancer cell survival. However, accumulating mechanistic evidence of T cell and cancer cell metabolism has gradually revealed that controlling the metabolic pathways of either type of cell can overcome T cell dysfunction and reprogram the metabolic balance in the tumor microenvironment. Here, we summarize the role of immune metabolism in T cell-based immune surveillance and cancer immune escape. This new concept has boosted the development of combination therapy and predictive biomarkers of immune checkpoint inhibitors.
    Keywords:  biomarker; combination therapy; energy metabolism; immune checkpoint; mitochondria
  15. Metabolites. 2020 Jul 08. pii: E279. [Epub ahead of print]10(7):
      Regulatory T cells (Tregs) are capable of suppressing excessive immune responses to prevent autoimmunity and chronic inflammation. Decreased numbers of Tregs and impaired suppressive function are associated with the progression of atherosclerosis, a chronic inflammatory disease of the arterial wall and the leading cause of cardiovascular disease. Therefore, therapeutic strategies to improve Treg number or function could be beneficial to preventing atherosclerotic disease development. A growing body of evidence shows that intracellular metabolism of Tregs is a key regulator of their proliferation, suppressive function, and stability. Here we evaluate the role of Tregs in atherosclerosis, their metabolic regulation, and the links between their metabolism and atherosclerosis.
    Keywords:  Foxp3; T cells; Tregs; atherosclerosis; hypercholesterolemia; immunometabolism; metabolism
  16. Nat Immunol. 2020 Jul 06.
      In response to pathogenic threats, naive T cells rapidly transition from a quiescent to an activated state, yet the underlying mechanisms are incompletely understood. Using a pulsed SILAC approach, we investigated the dynamics of mRNA translation kinetics and protein turnover in human naive and activated T cells. Our datasets uncovered that transcription factors maintaining T cell quiescence had constitutively high turnover, which facilitated their depletion following activation. Furthermore, naive T cells maintained a surprisingly large number of idling ribosomes as well as 242 repressed mRNA species and a reservoir of glycolytic enzymes. These components were rapidly engaged following stimulation, promoting an immediate translational and glycolytic switch to ramp up the T cell activation program. Our data elucidate new insights into how T cells maintain a prepared state to mount a rapid immune response, and provide a resource of protein turnover, absolute translation kinetics and protein synthesis rates in T cells (
  17. Immunity. 2020 Jul 02. pii: S1074-7613(20)30265-X. [Epub ahead of print]
      Tissue-resident memory (Trm) CD8+ T cells mediate protective immunity in barrier tissues, but the cues promoting Trm cell generation are poorly understood. Sensing of extracellular adenosine triphosphate (eATP) by the purinergic receptor P2RX7 is needed for recirculating CD8+ T cell memory, but its role for Trm cells is unclear. Here we showed that P2RX7 supported Trm cell generation by enhancing CD8+ T cell sensing of TGF-β, which was necessary for tissue residency. P2RX7-deficient Trm cells progressively decayed in non-lymphoid tissues and expressed dysregulated Trm-specific markers. P2RX7 was required for efficient re-expression of the receptor TGF-βRII through calcineurin signaling. Forced Tgfbr2 expression rescued P2RX7-deficient Trm cell generation, and TGF-β sensitivity was dictated by P2RX7 agonists and antagonists. Forced Tgfbr2 also rescued P2RX7-deficient Trm cell mitochondrial function. Sustained P2RX7 signaling was required for long-term Trm cell maintenance, indicating that P2RX7 signaling drives induction and CD8+ T cell durability in barrier sites.
    Keywords:  P2RX7; TGF-β; eATP; memory CD8(+) T cells; non-lymphoid tissue
  18. Elife. 2020 Jul 07. pii: e54854. [Epub ahead of print]9
      Failed T cell-based immunotherapies in the presence of genomic alterations in antigen presentations pathways may be overcome by NK cell-based immunotherapy. This approach may still be limited by the presence of immunosuppressive myeloid populations. Here, we demonstrate that NK cells (haNKs) engineered to express a PD-L1 chimeric antigen receptor (CAR) haNKs killed a panel of human and murine head and neck cancer cells at low effector-to-target ratios in a PD-L1-dependent fashion. Treatment of syngeneic tumors resulted in CD8 and PD-L1-dependent tumor rejection or growth inhibition and a reduction in myeloid cells endogenously expressing high levels of PD-L1. Treatment of xenograft tumors resulted in PD-L1-dependent tumor growth inhibition. PD-L1 CAR haNKs reduced levels of macrophages and other myeloid cells endogenously expressing high PD-L1 in peripheral blood from patients with head and neck cancer. The clinical study of PD-L1 CAR haNKs is warranted.
    Keywords:  NK cells; PD-L1; chimerica antigen receptor; human; immunology; inflammation; mouse; myeloid; syngeneic; xenograft
  19. Immunity. 2020 Jul 02. pii: S1074-7613(20)30264-8. [Epub ahead of print]
      Type I interferon (IFN) response is commonly recognized as the main signaling activity of STING. Here, we generate the Sting1S365A/S365A mutant mouse that precisely ablates IFN-dependent activities while preserving IFN-independent activities of STING. StingS365A/S365A mice protect against HSV-1 infection, despite lacking the STING-mediated IFN response. This challenges the prevailing view and suggests that STING controls HSV-1 infection through IFN-independent activities. Transcriptomic analysis reveals widespread IFN-independent activities of STING in macrophages and T cells, and STING activities in T cells are predominantly IFN independent. In mouse tumor models, T cells in the tumor experience substantial cell death that is in part mediated by IFN-independent activities of STING. We found that the tumor induces STING-mediated cell death in T cells to evade immune control. Our data demonstrate that mammalian STING possesses widespread IFN-independent activities that are important for restricting HSV-1 infection, tumor immune evasion and likely also adaptive immunity.
    Keywords:  HSV-1; IFN; STING; T cells; antiviral response; cancer immunology
  20. Mucosal Immunol. 2020 Jul 10.
      ILCs and T cells are closely related functionally but they significantly differ in their ability to circulate, expand, and renew. Cooperation and reciprocal functional regulation suggest that these cell types are more complementary than simply redundant during immune responses. How ILCs shape T-cell responses is strongly dependent on the tissue and inflammatory context. Likewise, indirect regulation of ILCs by adaptive immunity is induced by environmental cues such as the gut microbiota. Here, we review shared requirements for the development and function of both cell types and divergences in the orchestration of prototypic immune functions. We discuss the diversity of functional interactions between T cells and ILCs during homeostasis and immune responses. Identifying the location and the nature of the tissue microenvironment in which these interactions are taking place may uncover the remaining mysteries of their close encounters.
  21. Cell Rep. 2020 Jul 07. pii: S2211-1247(20)30829-9. [Epub ahead of print]32(1): 107848
      Immunotherapy shifted the paradigm of cancer treatment. The clinical approval of immune checkpoint blockade and adoptive cell transfer led to considerable success in several tumor types. However, for a significant number of patients, these therapies have proven ineffective. Growing evidence shows that the metabolic requirements of immune cells in the tumor microenvironment (TME) greatly influence the success of immunotherapy. It is well established that the TME influences energy consumption and metabolic reprogramming of immune cells, often inducing them to become tolerogenic and inefficient in cancer cell eradication. Increasing nutrient availability using pharmacological modulators of metabolism or antibodies targeting specific immune receptors are strategies that support energetic rewiring of immune cells and boost their anti-tumor capacity. In this review, we describe the metabolic features of the diverse immune cell types in the context of the TME and discuss how these immunomodulatory strategies could synergize with immunotherapy to circumvent its current limitations.
  22. EMBO J. 2020 Jul 01. 39(13): e104159
      γδ T cells with distinct properties develop in the embryonic and adult thymus and have been identified as critical players in a broad range of infections, antitumor surveillance, autoimmune diseases, and tissue homeostasis. Despite their potential value for immunotherapy, differentiation of γδ T cells in the thymus is incompletely understood. Here, we establish a high-resolution map of γδ T-cell differentiation from the fetal and adult thymus using single-cell RNA sequencing. We reveal novel sub-types of immature and mature γδ T cells and identify an unpolarized thymic population which is expanded in the blood and lymph nodes. Our detailed comparative analysis reveals remarkable similarities between the gene networks active during fetal and adult γδ T-cell differentiation. By performing a combined single-cell analysis of Sox13, Maf, and Rorc knockout mice, we demonstrate sequential activation of these factors during IL-17-producing γδ T-cell (γδT17) differentiation. These findings substantially expand our understanding of γδ T-cell ontogeny in fetal and adult life. Our experimental and computational strategy provides a blueprint for comparing immune cell differentiation across developmental stages.
    Keywords:  double negative progenitors; fetal and adult thymus; gamma delta T cells; gamma delta T‐cell differentiation; single‐cell RNA sequencing
  23. Nat Rev Cancer. 2020 Jul 06.
      Through the successes of checkpoint blockade and adoptive cellular therapy, immunotherapy has become an established treatment modality for cancer. Cellular metabolism has emerged as a critical determinant of the viability and function of both cancer cells and immune cells. In order to sustain prodigious anabolic needs, tumours employ a specialized metabolism that differs from untransformed somatic cells. This metabolism leads to a tumour microenvironment that is commonly acidic, hypoxic and/or depleted of critical nutrients required by immune cells. In this context, tumour metabolism itself is a checkpoint that can limit immune-mediated tumour destruction. Because our understanding of immune cell metabolism and cancer metabolism has grown significantly in the past decade, we are on the cusp of being able to unravel the interaction of cancer cell metabolism and immune metabolism in therapeutically meaningful ways. Although there are metabolic processes that are seemingly fundamental to both cancer and responding immune cells, metabolic heterogeneity and plasticity may serve to distinguish the two. As such, understanding the differential metabolic requirements of the diverse cells that comprise an immune response to cancer offers an opportunity to selectively regulate immune cell function. Such a nuanced evaluation of cancer and immune metabolism can uncover metabolic vulnerabilities and therapeutic windows upon which to intervene for enhanced immunotherapy.
  24. Proc Natl Acad Sci U S A. 2020 Jul 06. pii: 202002266. [Epub ahead of print]
      Signaling of 17β-estradiol (estrogen) through its two nuclear receptors, α and β (ERα, ERβ), is an important mechanism of transcriptional regulation. Although ERs are broadly expressed by cells of the immune system, the mechanisms by which they modulate immune responses remain poorly understood. ERβ-specific signaling is reduced in patients with chronic inflammatory diseases, including systemic lupus erythematosus and inflammatory bowel disease, and our previous work suggests that dysregulation of ERβ-specific signaling contributes to enhanced intestinal inflammation in female SAMP/YitFC mice, a spontaneous model of Crohn's disease-like ileitis. The present study builds on these prior observations to identify a nonredundant, immunoprotective role for ERβ-specific signaling in TGF-β-dependent regulatory T cell (Treg) differentiation. Using a strain of congenic SAMP mice engineered to lack global expression of ERβ, we observed dramatic, female-specific exacerbation of intestinal inflammation accompanied by significant reductions in intestinal Treg frequency and function. Impaired Treg suppression in the absence of ERβ was associated with aberrant overexpression of Tsc22d3 (GILZ), a glucocorticoid-responsive transcription factor not normally expressed in mature Tregs, and ex vivo data reveal that forced overexpression of GILZ in mature Tregs inhibits their suppressive function. Collectively, our findings identify a pathway of estrogen-mediated immune regulation in the intestine, whereby homeostatic expression of ERβ normally functions to limit Treg-specific expression of GILZ, thereby maintaining effective immune suppression. Our data suggest that transcriptional cross-talk between glucocorticoid and steroid sex hormone signaling represents an important and understudied regulatory node in chronic inflammatory disease.
    Keywords:  Crohn’s disease; estrogen; inflammation; inflammatory bowel disease; regulatory T cell
  25. Front Immunol. 2020 ;11 1109
      Chimeric antigen receptor (CAR) T cell therapies have demonstrated remarkable efficacy for the treatment of hematological malignancies. However, in patients with solid tumors, objective responses to CAR-T cell therapy remain sporadic and transient. A major obstacle for CAR-T cells is the intrinsic ability of tumors to evade immune responses. Advanced solid tumors are largely composed of desmoplastic stroma and immunosuppressive modulators, and characterized by aberrant cell proliferation and vascularization, resulting in hypoxia and altered nutrient availability. To mount a curative response after infusion, CAR-T cells must infiltrate the tumor, recognize their cognate antigen and perform their effector function in this hostile tumor microenvironment, to then differentiate and persist as memory T cells that confer long-term protection. Fortunately, recent advances in synthetic biology provide a wide set of tools to genetically modify CAR-T cells to overcome some of these obstacles. In this review, we provide a comprehensive overview of the key tumor intrinsic mechanisms that prevent an effective CAR-T cell antitumor response and we discuss the most promising strategies to prevent tumor escape to CAR-T cell therapy.
    Keywords:  adoptive cell transfer (ACT); chimeric antigen receptors (CAR); immunosuppressive tumor microenvironment; immunotherapy; inhibitory receptors; solid tumors
  26. Cancer Immunol Immunother. 2020 Jul 10.
      T-cell receptor (TCR)- and chimeric antigen receptor (CAR)-based adoptive cell transfer (ACT) has shown promising results in hematological malignancies, but remains immature in solid cancers. The challenges associated with identification of tumor-specific targets, the heterogenic antigen expression, limited T-cell trafficking to tumor sites and the hostile tumor microenvironment (TME), are all factors contributing to the limited efficacy of ACT therapies against solid tumors. Epigenetic priming of tumor cells and the microenvironment may be a way of overcoming these obstacles and improving the clinical efficacy of adoptive T-cell therapies in the future. Here, we review the current literature and suggest combining epigenetic modulators and ACT strategies as a way of augmenting the efficacy of TCR- and CAR-engineered T cells against solid tumors.
    Keywords:  Cancer immunotherapy; Cancer/testis antigens; Combination therapy; Epigenetic drugs; Genetically modified T cells; Solid tumors
  27. EMBO Mol Med. 2020 Jul 10. e12706
      The search for non-invasive systemic biomarkers of response to PD-L1/PD-1 blockade immunotherapy is currently a priority in oncoimmunology. In contrast to classical tumor biomarkers, the identification of clinically useful immunological biomarkers is certainly a challenge, as anti-cancer immune responses depend on the coordinated action of many cell types. Studies on the dynamics of systemic CD8 T-cell populations have provided indications that such biomarkers may have a place in clinical practice. However, the power of CD8 T-cell subsets to discriminate clinical responses in immunotherapy has so far proven to be limited. The systemic evaluation of CD8 T-cell regulators such as myeloid cells and CD4 T cells may provide the solution. Here we discuss the value of systemic quantification of CD4 T-cell subsets for patient selection in light of the results obtained by Prof. Kagamu's and our team. Our studies have independently demonstrated that the evaluation of the pre-treatment status of systemic CD4 immunity is a critical factor for the clinical outcome of PD-L1/PD-1 blockade therapy with robust predictive capacities.
  28. Nutrients. 2020 Jul 07. pii: E2021. [Epub ahead of print]12(7):
      Cholesterol, the most important sterol in mammals, helps maintain plasma membrane fluidity and is a precursor of bile acids, oxysterols, and steroid hormones. Cholesterol in the body is obtained from the diet or can be de novo synthetized. Cholesterol homeostasis is mainly regulated by the liver, where cholesterol is packed in lipoproteins for transport through a tightly regulated process. Changes in circulating lipoprotein cholesterol levels lead to atherosclerosis development, which is initiated by an accumulation of modified lipoproteins in the subendothelial space; this induces significant changes in immune cell differentiation and function. Beyond lesions, cholesterol levels also play important roles in immune cells such as monocyte priming, neutrophil activation, hematopoietic stem cell mobilization, and enhanced T cell production. In addition, changes in cholesterol intracellular metabolic enzymes or transporters in immune cells affect their signaling and phenotype differentiation, which can impact on atherosclerosis development. In this review, we describe the main regulatory pathways and mechanisms of cholesterol metabolism and how these affect immune cell generation, proliferation, activation, and signaling in the context of atherosclerosis.
    Keywords:  atherosclerosis; cholesterol; hematopoiesis; immune cells; inflammation; metabolism
  29. Cells. 2020 Jun 30. pii: E1588. [Epub ahead of print]9(7):
      T-cells have a natural ability to fight cancer cells in the tumour microenvironment. Due to thymic selection and tissue-driven immunomodulation, these cancer-fighting T-cells are generally low in number and exhausted. One way to overcome these issues is to genetically alter T-cells to improve their effectiveness. This process can involve introducing a receptor that has high affinity for a tumour antigen, with two promising candidates known as chimeric-antigen receptors (CARs), or T-cell receptors (TCRs) with high tumour specificity. This review focuses on the editing of immune cells to introduce such novel receptors to improve immune responses to cancer. These new receptors redirect T-cells innate killing abilities to the appropriate target on cancer cells. CARs are modified receptors that recognise whole proteins on the surface of cancer cells. They have been shown to be very effective in haematological malignancies but have limited documented efficacy in solid cancers. TCRs recognise internal antigens and therefore enable targeting of a much wider range of antigens. TCRs require major histocompatibility complex (MHC) restriction but novel TCRs may have broader antigen recognition. Moreover, there are multiple cell types which can be used as targets to improve the "off-the-shelf" capabilities of these genetic engineering methods.
    Keywords:  CAR-T; T-cells; TCR-T; cancer; immunotherapy
  30. Mech Ageing Dev. 2020 Jul 02. pii: S0047-6374(20)30104-4. [Epub ahead of print] 111308
      Senescent cells accumulate during aging in a variety of tissues. Although scarce, they could influence tissue function non-cell-autonomously via secretion of a range of factors in their neighborhood. Recent studies support a role of senescent cells in age-related morbidity, including neurodegenerative diseases, cardiovascular pathologies, cancers, aging-associated nephrological alterations, chronic pulmonary disease and osteoarthritis, indicating that senescent cells could represent an interesting target for therapeutic exploitation across a range of pathophysiological contexts. In this article, we review data available to indicate which cell types can undergo senescence within various mammalian tissue environments and how these processes may contribute to tissue-specific pathologies associated with old age. We also consider markers used to identify senescent cells in vitro and in vivo. The data discussed may serve as an important starting point for an extended definition of molecular and functional characteristics of senescent cells in different organs and may hence promote the development and refinement of targeting strategies aimed at removing senescent cells from aging tissues.
    Keywords:  SASP; age-related diseases; aging; in vivo senescence; senescent cell types
  31. Nat Commun. 2020 Jul 09. 11(1): 3421
      The OX40-OX40L pathway provides crucial co-stimulatory signals for CD4 T cell responses, however the precise cellular interactions critical for OX40L provision in vivo and when these occur, remains unclear. Here, we demonstrate that provision of OX40L by dendritic cells (DCs), but not T cells, B cells nor group 3 innate lymphoid cells (ILC3s), is critical specifically for the effector Th1 response to an acute systemic infection with Listeria monocytogenes (Lm). OX40L expression by DCs is regulated by cross-talk with NK cells, with IFNγ signalling to the DC to enhance OX40L in a mechanism conserved in both mouse and human DCs. Strikingly, DC expression of OX40L is redundant in a chronic intestinal Th1 response and expression by ILC3s is necessary. Collectively these data reveal tissue specific compartmentalisation of the cellular provision of OX40L and define a mechanism controlling DC expression of OX40L in vivo.
  32. Biol Blood Marrow Transplant. 2020 Jul 02. pii: S1083-8791(20)30395-5. [Epub ahead of print]
      Immune effector cell (IEC) therapy is emerging as a promising approach in the field of cancer immunotherapy. Clinical IEC trials, predominantly using chimeric antigen receptor (CAR) T cells, have shown excellent responses in CD19 positive B cell malignancies and multiple myeloma. In solid tumors, preclinical data are encouraging, but clinical data are in their infancy, and there are challenges in using CAR T therapy in this setting, including i) on-target off-tumor toxicity, ii) optimal target identification, iii) effective trafficking into bulky tumor tissue, and iv) resistance to tumor immune evasion mechanisms. Novel techniques and modifications are being explored, both in the pre-clinical and clinical setting, aiming to improve the treatment's efficiency and address the aforementioned obstacles to successful CAR T therapy in solid tumors. We will review these challenges in a clinically oriented approach and summarize clinical trials utilizing CAR T therapy in a variety of solid tumors.
    Keywords:  Cancer immunotherapy; Chimeric antigen receptor T cells; Immune effector cell therapy; Solid tumor; T cell receptor
  33. Cytotherapy. 2020 Jul 01. pii: S1465-3249(20)30751-9. [Epub ahead of print]
      BACKGROUND: An association between early CD4+ T cell immune reconstitution (CD4+ IR) and survival after T-replete allogeneic hematopoietic cell transplantation (HCT) has been previously reported. Here we report validation of this relationship in a separate cohort that included recipients of ex vivo T-cell-depleted (TCD) HCT. We studied the relationship between CD4+ IR and clinical outcomes.METHODS: A retrospective analysis of children/young adults receiving their first allogeneic HCT for any indication between January 2008 and December 2017 was performed. We related early CD4+ IR (defined as achieving >50 CD4+ T cells/µL on two consecutive measures within 100 days of HCT) to overall survival (OS), relapse, non-relapse mortality (NRM), event-free survival (EFS) and acute graft-versus-host disease (aGVHD). Fine and Gray competing risk models and Cox proportional hazard models were used.
    RESULTS: In this analysis, 315 patients with a median age of 10.4 years (interquartile range 5.0-16.5 years) were included. The cumulative incidence of CD4+ IR at 100 days was 66.7% in the entire cohort, 54.7% in TCD (N = 208, hazard ratio [HR] 0.47, P < 0.001), 90.0% in uCB (N = 40) and 89.6% in T-replete (N = 47) HCT recipients. In multi-variate analyses, not achieving early CD4+ IR was a predictor of inferior OS (HR 2.35, 95% confidence interval [CI] 1.46-3.79, P < 0.001) and EFS (HR 1.80, 95% CI 1.20-2.69, P = 0.004) and increased NRM (HR 6.58, 95% CI 2.82-15.38, P < 0.001). No impact of CD4+ IR on relapse or aGVHD was found. Within the TCD group, similar associations were observed.
    CONCLUSION: In this HCT cohort, including recipients of TCD HCT, we confirmed that early CD4+ IR was an excellent predictor of outcomes. Finding strategies to predict or improve CD4+ IR may influence outcomes.
    Keywords:  CD4 T Cells; Hematopoietic transplant; Pediatric; T-cell reconstitution; immune reconstitution
  34. Nat Commun. 2020 07 06. 11(1): 3434
      The immune system of patients infected by SARS-CoV-2 is severely impaired. Detailed investigation of T cells and cytokine production in patients affected by COVID-19 pneumonia are urgently required. Here we show that, compared with healthy controls, COVID-19 patients' T cell compartment displays several alterations involving naïve, central memory, effector memory and terminally differentiated cells, as well as regulatory T cells and PD1+CD57+ exhausted T cells. Significant alterations exist also in several lineage-specifying transcription factors and chemokine receptors. Terminally differentiated T cells from patients proliferate less than those from healthy controls, whereas their mitochondria functionality is similar in CD4+ T cells from both groups. Patients display significant increases of proinflammatory or anti-inflammatory cytokines, including T helper type-1 and type-2 cytokines, chemokines and galectins; their lymphocytes produce more tumor necrosis factor (TNF), interferon-γ, interleukin (IL)-2 and IL-17, with the last observation implying that blocking IL-17 could provide a novel therapeutic strategy for COVID-19.
  35. Cancers (Basel). 2020 Jul 07. pii: E1826. [Epub ahead of print]12(7):
      Unlike traditional cancer therapies, such as surgery, radiation and chemotherapy that are typically non-specific, cancer immunotherapy harnesses the high specificity of a patient's own immune system to selectively kill cancer cells. The immune system is the body's main cancer surveillance system, but cancers may evade destruction thanks to various immune-suppressing mechanisms. We therefore need to deploy various immunotherapy-based strategies to help bolster the anti-tumour immune responses. These include engineering T cells to express chimeric antigen receptors (CARs) to specifically recognise tumour neoantigens, inactivating immune checkpoints, oncolytic viruses and dendritic cell (DC) vaccines, which have all shown clinical benefit in certain cancers. However, treatment efficacy remains poor due to drug-induced adverse events and immunosuppressive tendencies of the tumour microenvironment. Recent preclinical studies have unveiled novel therapies such as anti-cathepsin antibodies, galectin-1 blockade and anti-OX40 agonistic antibodies, which may be utilised as adjuvant therapies to modulate the tumour microenvironment and permit more ferocious anti-tumour immune response.
    Keywords:  CAR-T cell; OX40; cathepsin D; checkpoint inhibitor; dendritic cell vaccines; drug resistance; galectin-1; immunosuppression; oncolytic viruses; tumour-induced immune evasion
  36. Scand J Immunol. 2020 Jul 08. e12929
      After prolonged extracorporeal multiplication in physiological culture media, there can be curative infusions of a cancer patient's own cytotoxic T-cells (adoptive T cell transfer; ACT), which must achieve efficient activation in potentially adverse tumor microenvironments. With spectacular, yet irregular, success, improvements are needed. Developing lymphoid cells are biologically selected, not only for "near-self" reactivity (positive selection), but also to avoid self-reactivity (negative selection). Thus, success requires harnessing near-self cells while avoiding extreme autoimmune phenomena. Abrupt metabolic changes accompanying T-cell activation to leave the G0 stage and enter the G1 stage of the cell cycle (e.g. enhanced glycolysis) are accompanied by increased transcription of the G0S9 gene that mediates salvage synthesis of NAD+ from nicotinamide; the latter has recently been shown to increase the efficiency of ACT. Despite these theoretical and experimental advances, there has not been parallel progress in simulating in vivo conditions with culture media that were initially formulated for their positive benefits for tumor cell lines (cell survival and proliferation). Yet for lymphoid cells, inhibition or death (i.e. immunological tolerance) is as important as their activation and proliferation (immunological response). Thus, use of media optimized for the latter may mask the former. The resilience of established culture protocols may have been partly politically driven. However, unphysiological conditions have sometimes yielded fortuitous insights. Optimization of culture media for specific tissues must consider the nature of problems addressed in research settings and the need to avoid mishaps in clinical settings.
    Keywords:  RNA synthesis; cancer; complement; immunotherapy; innate immunity; lectin; near-self reactivity; xenogeneic serum
  37. Cancers (Basel). 2020 Jul 02. pii: E1757. [Epub ahead of print]12(7):
      One of the greatest challenges in the cancer immunotherapy field is the need to biologically rationalize and broaden the clinical utility of immune checkpoint inhibitors (ICIs). The balance between metabolism and immune response has critical implications for overcoming the major weaknesses of ICIs, including their lack of universality and durability. The last decade has seen tremendous advances in understanding how the immune system's ability to kill tumor cells requires the conspicuous metabolic specialization of T-cells. We have learned that cancer cell-associated metabolic activities trigger shifts in the abundance of some metabolites with immunosuppressory roles in the tumor microenvironment. Yet very little is known about the tumor cell-intrinsic metabolic traits that control the immune checkpoint contexture in cancer cells. Likewise, we lack a comprehensive understanding of how systemic metabolic perturbations in response to dietary interventions can reprogram the immune checkpoint landscape of tumor cells. We here review state-of-the-art molecular- and functional-level interrogation approaches to uncover how cell-autonomous metabolic traits and diet-mediated changes in nutrient availability and utilization might delineate new cancer cell-intrinsic metabolic dependencies of tumor immunogenicity. We propose that clinical monitoring and in-depth molecular evaluation of the cancer cell-intrinsic metabolic traits involved in primary, adaptive, and acquired resistance to cancer immunotherapy can provide the basis for improvements in therapeutic responses to ICIs. Overall, these approaches might guide the use of metabolic therapeutics and dietary approaches as novel strategies to broaden the spectrum of cancer patients and indications that can be effectively treated with ICI-based cancer immunotherapy.
    Keywords:  diet; immune checkpoint inhibitors; immune checkpoints; metabolism; nutrition
  38. Immunol Med. 2020 Jul 09. 1-6
      Cancer immunotherapy has a long developmental history, beginning with William Coley's first bacterial mixture ('Coley's toxin') in 1891, which led to the development of nonspecific immunotherapy. After the research team of Thierry Boon succeeded in isolating the first melanoma antigen gene (MAGE-1) and identifying its major histocompatibility complex-restricted peptide in 1991, many kinds of cancer antigens were successively identified and so-called cancer vaccines were clinically tested. Although cancer vaccine therapy is expected to be the new cancer immunotherapy, it is currently unable to yield sufficient therapeutic effects when used alone and has thus not yet been approved as a drug. Meanwhile, various types of cell therapies, including tumor-infiltrating lymphocyte therapy, T-cell receptor-engineered T-cell therapy, and chimeric antigen receptor T-cell therapy, have shown remarkable clinical efficacy. Additionally, the discovery of immune checkpoint molecules has led to the success of immune checkpoint inhibitors, and cancer immunotherapy has now become a major pillar of cancer treatment. Currently, there are high expectations for the development of personalized neoantigen vaccines and T-cell therapies. The era of personalized cancer immunotherapy combined with immune checkpoint inhibitors is expected to arrive circa 2030.
    Keywords:  Cancer immunotherapy; immune checkpoint inhibitor; personalized immunotherapy; specific immunotherapy; tumor antigen
  39. Int J Mol Sci. 2020 Jul 06. pii: E4780. [Epub ahead of print]21(13):
      The regulation of hematopoietic stem cell (HSC) fate decision, whether they keep quiescence, self-renew, or differentiate into blood lineage cells, is critical for maintaining the immune system throughout one's lifetime. As HSCs are exposed to age-related stress, they gradually lose their self-renewal and regenerative capacity. Recently, many reports have implicated signaling pathways in the regulation of HSC fate determination and malignancies under aging stress or pathophysiological conditions. In this review, we focus on the current understanding of signaling pathways that regulate HSC fate including quiescence, self-renewal, and differentiation during aging, and additionally introduce pharmacological approaches to rescue defects of HSC fate determination or hematopoietic malignancies by kinase signaling pathways.
    Keywords:  aging; differentiation; hematopoietic stem cell; kinase inhibitor; quiescence; self-renewal
  40. Eur J Haematol. 2020 Jul 06.
      OBJECTIVES: Testicular diffuse large B-cell lymphoma (T-DLBCL) is a rare and aggressive extranodal lymphoma. We have previously shown that high content of tumor-infiltrating lymphocytes (TILs) and PD-1 expressing TILs associate with better survival in T-DLBCL. In this study, we have further characterized distinct TIL subtypes and their proportions in association with patient demographics and survival.METHODS: We used multiplex immunohistochemistry (mIHC) to characterize TIL phenotypes, including cytotoxic T-cells (CTLs) (CD8⁺, OX40⁺, Granzyme B⁺, Ki-67+ , LAG-3⁺, TIM-3⁺, PD-1⁺), CD4+ T-cells (CD3+ , CD4+ , TIM-3+ , LAG-3+ ), regulatory T-cells (Tregs; CD3+ , CD4+ , FoxP3+ ), and T helper 1 cells (Th1; CD3+ , CD4+ , T-bet+ ) in 79 T-DLBCLs, and correlated the findings with patient demographics and outcome.
    RESULTS: We observed a substantial variation in TIL phenotypes between the patients. The most prominent CD8+ TILs were Ki-67+ and TIM-3+ CTLs, whereas the most prominent CD4+ TILs were FoxP3⁺ Tregs. Despite the overall favorable prognostic impact of high TIL content, we found a subpopulation of T-bet⁺FoxP3+ Tregs that had a significant adverse impact on survival. Lower content of CTLs with activated or exhausted phenotypes correlated with aggressive clinical features.
    CONCLUSIONS: Our results demonstrate significant variation in TIL phenotypes and emphasize the adverse prognostic impact of Tregs in T-DLBCL.
    Keywords:  Tumor-infiltrating lymphocyte; lymphoma; regulatory T-cell; testicular diffuse large B-cell lymphoma
  41. Crit Rev Oncol Hematol. 2020 Jun 18. pii: S1040-8428(20)30169-4. [Epub ahead of print]153 103031
      Immune checkpoints are the regulators of the immune system, which include stimulatory and inhibitory receptors. They play substantial roles in the maintenance of immune system homeostasis and the prevention of autoimmunity and cancer. In the current review, immune checkpoints roles are surveyed in the initiation, progression, and treatment of blood malignancies. The significant roles of immune checkpoints are discussed as clinical markers in the diagnosis and prognosis of a plethora of blood malignancies and also as potential targets for the treatment of these malignancies. It could be concluded that the regulation of immune checkpoints in various blood cancers can be employed as a novel strategy to obtain effective results in leukemia treatment and introduce immune checkpoint inhibitors as sufficient weapons against blood cancers in the future.
    Keywords:  Blood cancers; Cancer treatment; Human immune system; Immune checkpoint
  42. Tissue Eng Part B Rev. 2020 Jul 07.
      The immune system plays a critical role in directing tissue repair and regeneration outcomes. Tissue engineering technologies that are designed to promote new tissue growth will therefore be impacted by immune factors that are present in patients both locally at the site of intervention and systemically. The immune state of patients can be influenced by many factors including infection, nutrition, and other disease comorbidities. As a result, the immune state is highly variable and may be a source of variability in tissue engineered products in the clinic that is not found in preclinical models. In this review, we will summarize key immune cells and evidence of their activity in tissue repair and potential in tissue engineering systems. We also discuss how clinical translation of tissue engineering strategies, in particular stem cells, helped elucidate the importance of the immune system. With increased understanding of the immune system role in repair and tissue engineering systems it will likely become a therapeutic target and component of future therapies.
  43. Nat Commun. 2020 Jul 10. 11(1): 3445
      Despite their very close structural similarity, CxxC/S-type (class I) glutaredoxins (Grxs) act as oxidoreductases, while CGFS-type (class II) Grxs act as FeS cluster transferases. Here we show that the key determinant of Grx function is a distinct loop structure adjacent to the active site. Engineering of a CxxC/S-type Grx with a CGFS-type loop switched its function from oxidoreductase to FeS transferase. Engineering of a CGFS-type Grx with a CxxC/S-type loop abolished FeS transferase activity and activated the oxidative half reaction of the oxidoreductase. The reductive half-reaction, requiring the interaction with a second GSH molecule, was enabled by switching additional residues in the active site. We explain how subtle structural differences, mostly depending on the structure of one particular loop, act in concert to determine Grx function.
  44. Aging Cell. 2020 Jul 06. e13187
      Advancing age is a major risk factor for developing heart disease, and the biological processes contributing to aging are currently under intense investigation. Autophagy is an important cellular quality control mechanism that is reduced in tissues with age but the molecular mechanisms underlying the age-associated defects in autophagy remain poorly characterized. Here, we have investigated how the autophagic process is altered in aged mouse hearts. We report that autophagic activity is reduced in aged hearts due to a reduction in autophagosome formation. Gene expression profile analysis to evaluate changes in autophagy regulators uncovered a reduction in Atg9b transcript and protein levels. Atg9 proteins are critical in delivering membrane to the growing autophagosome, and siRNA knockdown of Atg9b in cells confirmed a reduction in autophagosome formation. Autophagy is also the main pathway involved in eliminating dysfunctional mitochondria via a process known as mitophagy. The E3 ubiquitin ligase Parkin plays a key role in labeling mitochondria for mitophagy. We also found increased levels of Parkin-positive mitochondria in the aged hearts, an indication that they have been labeled for mitophagy. In contrast, Nrf1, a major transcriptional regulator of mitochondrial biogenesis, was significantly reduced in aged hearts. Additionally, our data showed reduced Drp1-mediated mitochondrial fission and formation of enlarged mitochondria in the aged heart. Overall, our findings suggest that cardiac aging is associated with reduced autophagosome number, decreased mitochondrial turnover, and formation of megamitochondria.
    Keywords:  Atg9; Parkin; aging; autophagy; heart; mitochondria; mitophagy
  45. Immunotherapy. 2020 Jul 07.
      The major current focus on treating rheumatoid arthritis is to put an end to long-term treatments and instead, specifically block widespread immunosuppression by developing antigen-specific tolerance, while also permitting an intact immune response toward other antigens to occur. There have been promising preclinical findings regarding adoptive Treg cells immunotherapy with a critically responsible function in the prevention of autoimmunity, tissue repair and regeneration, which make them an attractive candidate to develop effective therapeutic approaches to achieve this interesting concept in many human immune-mediated diseases, such as rheumatoid arthritis. Ex vivo or invivo manipulation protocols are not only utilized to correct Treg cells defect, but also to benefit from their specific immunosuppressive properties by identifying specific antigens that are expressed in the inflamedjoint. The methods able to address these deficiencies can be considered as a target for immunity interventions to restore appropriate immune function.
    Keywords:  Foxp3; Treg; Treg cell immunotherapy; Treg cell modulation; adoptive cell therapy; expansion of Treg cell; immunotherapy; induced antigen-specific Treg cell; regulatory T cell; rheumatoid arthritis
  46. Nat Rev Nephrol. 2020 Jul 08.
      ATP and its ultimate degradation product adenosine are potent extracellular signalling molecules that elicit a variety of pathophysiological functions in the kidney through the activation of P2 and P1 purinergic receptors, respectively. Extracellular purines can modulate immune responses, balancing inflammatory processes and immunosuppression; indeed, alterations in extracellular nucleotide and adenosine signalling determine outcomes of inflammation and healing processes. The functional activities of ectonucleotidases such as CD39 and CD73, which hydrolyse pro-inflammatory ATP to generate immunosuppressive adenosine, are therefore pivotal in acute inflammation. Protracted inflammation may result in aberrant adenosinergic signalling, which serves to sustain inflammasome activation and worsen fibrotic reactions. Alterations in the expression of ectonucleotidases on various immune cells, such as regulatory T cells and macrophages, as well as components of the renal vasculature, control purinergic receptor-mediated effects on target tissues within the kidney. The role of CD39 as a rheostat that can have an impact on purinergic signalling in both acute and chronic inflammation is increasingly supported by the literature, as detailed in this Review. Better understanding of these purinergic processes and development of novel drugs targeting these pathways could lead to effective therapies for the management of acute and chronic kidney disease.