bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021‒03‒14
fifteen papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. Cold Spring Harb Perspect Biol. 2021 Mar 08. pii: a038117. [Epub ahead of print]
      Resident memory CD8+ T (Trm) cells permanently reside in nonlymphoid tissues where they act as a first line of defense against recurrent pathogens. How and when antigen-inexperienced CD8+ T cells differentiate into Trm has been a topic of major interest, as knowledge on how to steer this process may be exploited in the development of vaccines and anticancer therapies. Here, we first review the current understanding of the early signals that CD8+ T cells receive before they have entered the tissue and that govern their capacity to develop into tissue-resident memory T cells. Subsequently, we discuss the tissue-derived factors that promote Trm maturation in situ. Combined, these data sketch a model in which a subset of responding T cells develops a heightened capacity to respond to local cues present in the tissue microenvironment, which thereby imprints their ability to contribute to the tissue-resident memory CD8+ T-cell pool that provide local control against pathogens.
  2. Exp Mol Med. 2021 Mar 12.
      T cells of the γδ lineage are unconventional T cells with functions not restricted to MHC-mediated antigen presentation. Because of their broad antigen specificity and NK-like cytotoxicity, γδ T-cell importance in tumor immunology has been emphasized. However, some γδ T-cell subsets, especially those expressing IL-17, are immunosuppressive or tumor-promoting cells. Their cytokine profile and cytotoxicity are seemingly determined by cross-talk with microenvironment components, not by the γδTCR chain. Furthermore, much about the TCR antigen of γδ T cells remains unknown compared with the extreme diversity of their TCR chain pairs. Thus, the investigation and application of γδ T cells have been relatively difficult. Nevertheless, γδ T cells remain attractive targets for antitumor therapy because of their independence from MHC molecules. Because tumor cells have the ability to evade the immune system through MHC shedding, heterogeneous antigens, and low antigen spreading, MHC-independent γδ T cells represent good alternative targets for immunotherapy. Therefore, many approaches to using γδ T cells for antitumor therapy have been attempted, including induction of endogenous γδ T cell activation, adoptive transfer of expanded cells ex vivo, and utilization of chimeric antigen receptor (CAR)-T cells. Here, we discuss the function of γδ T cells in tumor immunology and their application to cancer therapy.
  3. Curr Opin Biotechnol. 2021 Mar 03. pii: S0958-1669(21)00031-8. [Epub ahead of print]68 240-250
      T cells shape immune responses in cancer, autoimmunity and infection, in which CD4+ T helper (Th) and CD8+ T cells mediate effector responses that are suppressed by regulatory T (Treg) cells. The balance between effector T cell and Treg cell function orchestrates immune homeostasis and functional programming, with important contributions to the onset and progression of cancer. Cellular metabolism is dynamically rewired in T cells in response to environmental cues and dictates various aspects of T cell function. In this review, we summarize recent findings on how cellular metabolism modulates effector T cell and Treg cell functional fitness in homeostasis and cancer immunity, and highlight the therapeutic implications of targeting immunometabolic pathways for cancer and other diseases.
  4. Nat Rev Drug Discov. 2021 Mar 08.
      The success of checkpoint inhibitors has accelerated the clinical implementation of a vast mosaic of single agents and combination immunotherapies. However, the lack of clinical translation for a number of immunotherapies as monotherapies or in combination with checkpoint inhibitors has clarified that new strategies must be employed to advance the field. The next chapter of immunotherapy should examine the immuno-oncology therapeutic failures, and consider the complexity of immune cell-cancer cell interactions to better design more effective anticancer drugs. Herein, we briefly review the history of immunotherapy and checkpoint blockade, highlighting important clinical failures. We discuss the critical aspects - beyond T cell co-receptors - of immune processes within the tumour microenvironment (TME) that may serve as avenues along which new therapeutic strategies in immuno-oncology can be forged. Emerging insights into tumour biology suggest that successful future therapeutics will focus on two key factors: rescuing T cell homing and dysfunction in the TME, and reappropriating mononuclear phagocyte function for TME inflammatory remodelling. New drugs will need to consider the complex cell networks that exist within tumours and among cancer types.
  5. Cell Metab. 2021 Mar 03. pii: S1550-4131(21)00071-1. [Epub ahead of print]
      Understanding the mechanisms underlying how T cells become dysfunctional in a tumor microenvironment (TME) will greatly benefit cancer immunotherapy. We found that increased CD36 expression in tumor-infiltrating CD8+ T cells, which was induced by TME cholesterol, was associated with tumor progression and poor survival in human and murine cancers. Genetic ablation of Cd36 in effector CD8+ T cells exhibited increased cytotoxic cytokine production and enhanced tumor eradication. CD36 mediated uptake of fatty acids by tumor-infiltrating CD8+ T cells in TME, induced lipid peroxidation and ferroptosis, and led to reduced cytotoxic cytokine production and impaired antitumor ability. Blocking CD36 or inhibiting ferroptosis in CD8+ T cells effectively restored their antitumor activity and, more importantly, possessed greater antitumor efficacy in combination with anti-PD-1 antibodies. This study reveals a new mechanism of CD36 regulating the function of CD8+ effector T cells and therapeutic potential of targeting CD36 or inhibiting ferroptosis to restore T cell function.
    Keywords:  CD36; CD8(+) T cells; ferroptosis; lipid peroxidation
  6. Cell Rep. 2021 Mar 09. pii: S2211-1247(21)00145-5. [Epub ahead of print]34(10): 108831
      Although T cell expansion depends on glycolysis, T effector cell differentiation requires signaling via the production of reactive oxygen species (ROS). Because the pentose phosphate pathway (PPP) regulates ROS by generating nicotinamide adenine dinucleotide phosphate (NADPH), we examined how PPP blockade affects T cell differentiation and function. Here, we show that genetic ablation or pharmacologic inhibition of the PPP enzyme 6-phosphogluconate dehydrogenase (6PGD) in the oxidative PPP results in the generation of superior CD8+ T effector cells. These cells have gene signatures and immunogenic markers of effector phenotype and show potent anti-tumor functions both in vitro and in vivo. In these cells, metabolic reprogramming occurs along with increased mitochondrial ROS and activated antioxidation machinery to balance ROS production against oxidative damage. Our findings reveal a role of 6PGD as a checkpoint for T cell effector differentiation/survival and evidence for 6PGD as an attractive metabolic target to improve tumor immunotherapy.
    Keywords:  6PGD; effector T cells; metabolism; pentose phosphate pathway; reactive oxygen species; tumor immunotherapy
  7. Blood Adv. 2021 Mar 23. 5(6): 1605-1616
      Hematopoietic cell transplantation is a critical curative approach for many blood disorders. However, obtaining grafts with sufficient numbers of hematopoietic stem cells (HSCs) that maintain long-term engraftment remains challenging; this is due partly to metabolic modulations that restrict the potency of HSCs outside of their native environment. To address this, we focused on mitochondria. We found that human HSCs are heterogeneous in their mitochondrial activity as measured by mitochondrial membrane potential (MMP) even within the highly purified CD34+CD38-CD45RA-CD90+CD49f+ HSC population. We further found that the most potent HSCs exhibit the lowest mitochondrial activity in the population. We showed that the frequency of long-term culture initiating cells in MMP-low is significantly greater than in MMP-high CD34+CD38-CD45RA-CD90+ (CD90+) HSCs. Notably, these 2 populations were distinct in their long-term repopulating capacity when transplanted into immunodeficient mice. The level of chimerism 7 months posttransplantation was >50-fold higher in the blood of MMP-low relative to MMP-high CD90+ HSC recipients. Although more than 90% of both HSC subsets were in G0, MMP-low CD90+ HSCs exhibited delayed cell-cycle priming profile relative to MMP-high HSCs. These functional differences were associated with distinct mitochondrial morphology; MMP-low in contrast to MMP-high HSCs contained fragmented mitochondria. Our findings suggest that the lowest MMP level selects for the most potent, likely dormant, stem cells within the highly purified HSC population. These results identify a new approach for isolating highly potent human HSCs for further clinical applications. They also implicate mitochondria in the intrinsic regulation of human HSC quiescence and potency.
  8. Front Cell Dev Biol. 2021 ;9 638037
      CD39 and CD73 are ectoenzymes that dephosphorylate ATP into its metabolites; ADP, AMP, and adenosine, and thus are considered instrumental in the development of immunosuppressive microenvironments. We have previously shown that within the CD8+ T cell population, naïve and memory cells express the CD73 ectonucleotidase, while terminally differentiated effector cells are devoid of this enzyme. This evidence suggests that adenosine might exert an autocrine effect on CD8+ T cells during T cell differentiation. To study the possible role of CD73 and adenosine during this process, we compared the expression of the adenosinergic signaling components, the phenotype, and the functional properties between CD73-deficient and WT CD8+ T cells. Upon activation, we observed an upregulation of CD73 expression in CD8+ T cells along with an upregulation of the adenosine A2A receptor. Interestingly, when we differentiated CD8+ T cells to Tc1 cells in vitro, we observed that these cells produce adenosine and that CD73-deficient cells present a higher cytotoxic potential evidenced by an increase in IFN-γ, TNF-α, and granzyme B production. Moreover, CD73-deficient cells presented a increased glucose uptake and higher mitochondrial respiration, indicating that this ectonucleotidase restrict the mitochondrial capacity in CD8+ T cells. In agreement, when adoptively transferred, antigen-specific CD73-deficient CD8+ T cells were more effective in reducing the tumor burden in B16.OVA melanoma-bearing mice and presented lower levels of exhaustion markers than wild type cells. All these data suggest an autocrine effect of CD73-mediated adenosine production, limiting differentiation and cytotoxic T cells' metabolic fitness.
    Keywords:  CD73/NT5E; CD8 T cell; antitumor activity; cytotoxic; metabolism
  9. Immunol Rev. 2021 Mar 07.
      Adaptive immunity to intracellular pathogens and tumors is mediated by antigen-experienced CD8 T cells. Individual naive CD8 T cells have the potential to differentiate into a diverse array of antigen-experienced subsets that exhibit distinct effector functions, life spans, anatomic positioning, and potential for regenerating an entirely new immune response during iterative pathogenic exposures. The developmental process by which activated naive cells undergo diversification involves regulation of chromatin structure and transcription but is not entirely understood. This review examines how alterations in chromatin structure, transcription factor binding, extracellular signals, and single-cell gene expression explain the differential development of distinct effector (TEFF ) and memory (TMEM ) CD8 T cell subsets. Special emphasis is placed on how Runx proteins function with additional transcription factors to pioneer changes in chromatin accessibility and drive transcriptional programs that establish the core attributes of cytotoxic T lymphocytes, subdivide circulating and non-circulating TMEM cell subsets, and govern terminal differentiation. The discussion integrates the roles of specific cytokine signals, transcriptional circuits and how regulation of individual nucleosomes and RNA polymerase II activity can contribute to the process of differentiation. A model that integrates many of these features is discussed to conceptualize how activated CD8 T cells arrive at their fates.
    Keywords:  CD8 T cell memory; Runx transcription factors; chromatin remodeling; nucleosome; transcriptional elongation; viral infection
  10. Curr Opin Pharmacol. 2021 Mar 05. pii: S1471-4892(21)00004-7. [Epub ahead of print]57 107-116
      Aging is associated with the highest risk for morbidity and mortality to chronic or metabolic diseases, which are present in 50% of the elderly. Improving metabolic and immune function of the elderly would improve quality of life and reduce the risk for all other diseases. Tissue-resident macrophages and the NLRP3 inflammasome are established drivers of inflammaging and metabolic dysfunction. Energy-sensing signaling pathways connect sterile and metabolic inflammation with cellular senescence and tissue dysfunction. We discuss recent advances in the immunometabolism field. Common themes revealed by recent publications include the alterations in metabolic signaling (SIRTUIN, AMPK, or mTOR pathways) in aged immune cells, the impact of senescence on inflammaging and tissue dysfunction, and the age-related changes in metabolic tissues, especially adipose tissue, as an immunological organ. Promising gerotherapeutics are candidates to broadly target nutrient and energy sensing, inflammatory and senescence pathways, and have potential to improve healthspan and treat age-related diseases.
    Keywords:  AMPK-mTOR pathway; Adipose tissue; Aging; Immunometabolism; Inflammaging; Macrophage; NAD metabolism; NLRP3 inflammasome; SIRTUIN pathway
  11. Front Immunol. 2021 ;12 630389
      The proprotein convertase enzyme FURIN promotes the proteolytic maturation of pro-proteins and thereby it serves as an important factor for maintaining cellular homeostasis. In T cells, FURIN is critical for maintaining the T regulatory cell dependent peripheral immune tolerance and intact T helper cell polarization. The enzymatic activity of FURIN is directly associated with its expression levels, but genetic determinants for cell-type specific Furin gene regulation have remained elusive. By exploring the histone acetyltransferase p300 binding patterns in T helper cells, a putative regulatory region at ca. 20kB upstream of Furin gene was identified. When this region was deleted with CRISPR/Cas9 the production of Furin mRNA was significantly reduced in activated mouse T cells. Genome-wide RNA profiling by sequencing revealed that the novel Furin regulator region also impacted the expression of several genes that have previously been associated with the Th1 type hall mark cytokine IFNγ regulation or function. Finally, Furin genetic regulatory region was found to specifically promote the secretion of IFNγ by activated T cells. In sum, our data unravels the presence of Furin expression regulatory region in T cells that has characteristics of a super-enhancer for Th1 cell fate.
    Keywords:  Furin regulation; interferon gamma; p300; proprotein convertase; super-enhancer
  12. Blood Adv. 2021 Mar 23. 5(6): 1594-1604
      Hematopoietic stem cells (HSCs) undergo self-renewal or differentiation to sustain lifelong hematopoiesis. HSCs are preserved in quiescence with low mitochondrial activity. Recent studies indicate that autophagy contributes to HSC quiescence through suppressing mitochondrial metabolism. However, it remains unclear whether autophagy is involved in the regulation of neonatal HSCs, which proliferate actively. In this study, we clarified the role of autophagy in neonatal HSCs using 2 types of autophagy-related gene 7 (Atg7)-conditional knockout mice: Mx1-Cre inducible system and Vav-Cre system. Atg7-deficient HSCs exhibited excess cell divisions with enhanced mitochondrial metabolism, leading to bone marrow failure at adult stage. However, Atg7 deficiency minimally affected hematopoiesis and metabolic state in HSCs at neonatal stage. In addition, Atg7-deficient neonatal HSCs exhibited long-term reconstructing activity, equivalent to wild-type neonatal HSCs. Taken together, autophagy is dispensable for stem cell function and hematopoietic homeostasis in neonates and provide a novel aspect into the role of autophagy in the HSC regulation.
  13. Blood. 2021 Mar 10. pii: blood.2020009309. [Epub ahead of print]
      Chimeric antigen receptor T cell (CAR-T cell) therapeutic efficacy is associated with long-term T cell persistence and acquisition of memory. Memory subset formation requires TCF-1, a master transcription factor for which few regulators have been identified. Here, we demonstrate using an immune-competent mouse model of B cell acute lymphoblastic leukemia (B-ALL) that Regnase-1 deficiency promotes TCF-1 expression to enhance CAR-T cell expansion and memory-like cell formation. This leads to improved CAR-T-mediated tumor clearance, sustained remissions, and protection against secondary tumor challenge. Phenotypic, transcriptional, and epigenetic profiling identified increased tumor-dependent programming of Regnase-1-deficient CAR-T cells into TCF-1+ precursor exhausted (TPEX) cells characterized by upregulation of both memory and exhaustion markers. Regnase-1 directly targets Tcf7 mRNA; its deficiency augments TCF-1 expression leading to the formation of TPEX that support long-term CAR-T cell persistence and function. Regnase-1 deficiency also reduces exhaustion and enhances the activity of TCF-1- CAR-T cells. We further validate these findings in human CAR-T cells, where Regnase-1 deficiency mediates enhanced tumor clearance in a xenograft B-ALL model. This is associated with increased persistence and expansion of a TCF-1+ CAR-T cell population. Our findings demonstrate pivotal roles of TPEX, Regnase-1, and TCF-1 in mediating CAR-T cell persistence and recall responses, and identify Regnase-1 as a modulator of human CAR-T cell longevity and potency that may be manipulated for improved therapeutic efficacy.
  14. Immunity. 2021 Mar 06. pii: S1074-7613(21)00084-4. [Epub ahead of print]
      Memory T cells are thought to rely on oxidative phosphorylation and short-lived effector T cells on glycolysis. Here, we investigated how T cells arrive at these states during an immune response. To understand the metabolic state of rare, early-activated T cells, we adapted mass cytometry to quantify metabolic regulators at single-cell resolution in parallel with cell signaling, proliferation, and effector function. We interrogated CD8+ T cell activation in vitro and in response to Listeria monocytogenes infection in vivo. This approach revealed a distinct metabolic state in early-activated T cells characterized by maximal expression of glycolytic and oxidative metabolic proteins. Cells in this transient state were most abundant 5 days post-infection before rapidly decreasing metabolic protein expression. Analogous findings were observed in chimeric antigen receptor (CAR) T cells interrogated longitudinally in advanced lymphoma patients. Our study demonstrates the utility of single-cell metabolic analysis by mass cytometry to identify metabolic adaptations of immune cell populations in vivo and provides a resource for investigations of metabolic regulation of immune responses across a variety of applications.
    Keywords:  CD8 T cell; T cell activation; immunometabolism; mass cytometry
  15. Cell Host Microbe. 2021 Mar 05. pii: S1931-3128(21)00084-6. [Epub ahead of print]
      CD4 T cell effector function is required for optimal containment of Mycobacterium tuberculosis (Mtb) infection. IFNɣ produced by CD4 T cells is a key cytokine that contributes to protection. However, lung-infiltrating CD4 T cells have a limited ability to produce IFNɣ, and IFNɣ plays a lesser protective role within the lung than at sites of Mtb dissemination. In a murine infection model, we observed that IFNɣ production by Mtb-specific CD4 T cells is rapidly extinguished within the granuloma but not within unaffected lung regions, suggesting localized immunosuppression. We identified a signature of TGFβ signaling within granuloma-infiltrating T cells in both mice and rhesus macaques. Selective blockade of TGFβ signaling in T cells resulted in an accumulation of terminally differentiated effector CD4 T cells, improved IFNɣ production within granulomas, and reduced bacterial burdens. These findings uncover a spatially localized immunosuppressive mechanism associated with Mtb infection and provide potential targets for host-directed therapy.
    Keywords:  IFNɣ; Mycobacterium tuberculosis; T cell function; TGFβ; adaptive immunity; granuloma; immune cell trafficking; immune suppression; lung inflammation; quantitative imaging