bims-imseme 2023-01-01 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2023–01–01
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Lymphoid tissue residency: A key to understand Tcf-1+PD-1+ T cells.
Targeting T-cell metabolism to boost immune checkpoint inhibitor therapy.
Regulation of effector and memory CD8 + T cell differentiation: a focus on orphan nuclear receptor NR4A family, transcription factor, and metabolism.
Short-chain fatty acid-mediated epigenetic modulation of inflammatory T cells in vitro.
T cell-responsive macroporous hydrogels for in situ T cell expansion and enhanced antitumor efficacy.
TGF-β1 suppresses the T-cell response in teleost fish by initiating Smad3- and Foxp3-mediated transcriptional networks.
Altered T cell infiltration and enrichment of leukocyte regulating pathways within aged skeletal muscle are associated impaired muscle function following influenza infection.
The ectonucleotidase CD39 identifies tumor-reactive CD8+ T cells predictive of immune checkpoint blockade efficacy in human lung cancer.
Mitochondria and peroxisomes: partners in autophagy.
AutophagosOMES: identification of autophagosomal cargo in CD4+ T cells by proteomics.
Metabolic adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments.
Modulating T-bet-promoted energy metabolism in pathogenic age/autoimmune-associated B cells ameliorates lupus autoimmunity.
CD8+ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor.

Front Immunol. 2022 ;13 1074698

Lymphoid tissue residency: A key to understand Tcf-1+PD-1+ T cells.

Chaoyu Ma, Nu Zhang.

  During chronic antigen exposure, a subset of exhausted CD8+ T cells differentiate into stem cell-like or progenitor-like T cells expressing both transcription factor Tcf-1 (T cell factor-1) and co-inhibitory receptor PD-1. These Tcf-1+ stem-like or progenitor exhausted T cells represent the key target for immunotherapies. Deeper understanding of the biology of Tcf-1+PD-1+ CD8+ T cells will lead to rational design of future immunotherapies. Here, we summarize recent findings about the migratory and resident behavior of Tcf-1+ T cells. Specifically, we will focus on TGF-β-dependent lymphoid tissue residency program of Tcf-1+ T cells, which may represent a key to understanding the differentiation and maintenance of Tcf-1+ stem-like CD8+ T cells during persistent antigen stimulation.

Keywords:  TCF-1; TGF-beta; chronic infection; lymph node; tissue-resident; tumor

DOI:  https://doi.org/10.3389/fimmu.2022.1074698
Front Immunol. 2022 ;13 1046755

Targeting T-cell metabolism to boost immune checkpoint inhibitor therapy.

Haohao Li, Alison Zhao, Menghua Li, Lizhi Shi, Qiuju Han, Zhaohua Hou.

  Immune checkpoint inhibitors (ICIs) have shown promising therapeutic effects in the treatment of advanced solid cancers, but their overall response rate is still very low for certain tumor subtypes, limiting their clinical scope. Moreover, the high incidence of drug resistance (including primary and acquired) and adverse effects pose significant challenges to the utilization of these therapies in the clinic. ICIs enhance T cell activation and reverse T cell exhaustion, which is a complex and multifactorial process suggesting that the regulatory mechanisms of ICI therapy are highly heterogeneous. Recently, metabolic reprogramming has emerged as a novel means of reversing T-cell exhaustion in the tumor microenvironment; there is increasing evidence that T cell metabolic disruption limits the therapeutic effect of ICIs. This review focuses on the crosstalk between T-cell metabolic reprogramming and ICI therapeutic efficacy, and summarizes recent strategies to improve drug tolerance and enhance anti-tumor effects by targeting T-cell metabolism alongside ICI therapy. The identification of potential targets for altering T-cell metabolism can significantly contribute to the development of methods to predict therapeutic responsiveness in patients receiving ICI therapy, which are currently unknown but would be of great clinical significance.

Keywords:  T cell metabolism; immune checkpoint; immune checkpoints inhibitor; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.1046755
Immunol Res. 2022 Dec 26.

Regulation of effector and memory CD8 + T cell differentiation: a focus on orphan nuclear receptor NR4A family, transcription factor, and metabolism.

Oladapo O Oladipo, Bernard O Adedeji, Samson P Adedokun, Jibriil A Gbadamosi, Marzuq Salaudeen.

  CD8 + T cells undergo rapid expansion followed by contraction and the development of memory cells after their receptors are activated. The development of immunological memory following acute infection is a complex phenomenon that involves several molecular, transcriptional, and metabolic mechanisms. As memory cells confer long-term protection and respond to secondary stimulation with strong effector function, understanding the mechanisms that influence their development is of great importance. Orphan nuclear receptors, NR4As, are immediate early genes that function as transcription factors and bind with the NBRE region of chromatin. Interestingly, the NBRE region of activated CD8 + T cells is highly accessible at the same time the expression of NR4As is induced. This suggests a potential role of NR4As in the early events post T cell activation that determines cell fate decisions. In this review, we will discuss the influence of NR4As on the differentiation of CD8 + T cells during the immune response to acute infection and the development of immunological memory. We will also discuss the signals, transcription factors, and metabolic mechanisms that control cell fate decisions. HIGHLIGHTS: Memory CD8 + T cells are an essential subset that mediates long-term protection after pathogen encounters. Some specific environmental cues, transcriptional factors, and metabolic pathways regulate the differentiation of CD8 + T cells and the development of memory cells. Orphan nuclear receptor NR4As are early genes that act as transcription factors and are highly expressed post-T cell receptor activation. NR4As influence the effector function and differentiation of CD8 + T cells and also control the development of immunological memory following acute infection.

Keywords:  Acute infection; Differentiation; Immunological memory; NR4A nuclear receptor; Transcription factors

DOI:  https://doi.org/10.1007/s12026-022-09353-1
Drug Deliv Transl Res. 2022 Dec 24.

Short-chain fatty acid-mediated epigenetic modulation of inflammatory T cells in vitro.

David A McBride, Nicholas C Dorn, Mina Yao, Wade T Johnson, Wei Wang, Nunzio Bottini, Nisarg J Shah.

  Short-chain fatty acids (SCFAs) are major metabolic products of indigestible polysaccharides in the gut and mediate the function of immune cells to facilitate homeostasis. The immunomodulatory effect of SCFAs has been attributed, at least in part, to the epigenetic modulation of immune cells through the inhibition the nucleus-resident enzyme histone deacetylase (HDAC). Among the downstream effects, SCFAs enhance regulatory T cells (Treg) over inflammatory T helper (Th) cells, including Th17 cells, which can be pathogenic. Here, we characterize the potential of two common SCFAs-butyrate and pentanoate-in modulating differentiation of T cells in vitro. We show that butyrate but not pentanoate exerts a concentration-dependent effect on Treg and Th17 differentiation. Increasing the concentration of butyrate suppresses the Th17-associated RORγtt and IL-17 and increases the expression of Treg-associated FoxP3. To effectively deliver butyrate, encapsulation of butyrate in a liposomal carrier, termed BLIPs, reduced cytotoxicity while maintaining the immunomodulatory effect on T cells. Consistent with these results, butyrate and BLIPs inhibit HDAC and promote a unique chromatin landscape in T cells under conditions that otherwise promote conversion into a pro-inflammatory phenotype. Motif enrichment analysis revealed that butyrate and BLIP-mediated suppression of Th17-associated chromatin accessibility corresponded with a marked decrease in bZIP family transcription factor binding sites. These results support the utility and further evaluation of BLIPs as an immunomodulatory agent for autoimmune disorders that are characterized by chronic inflammation and pathogenic inflammatory T cells.

Keywords:  Epigenetic modulation; Immunomodulation; Short-chain fatty acids; T cells

DOI:  https://doi.org/10.1007/s13346-022-01284-6
Biomaterials. 2022 Dec 16. pii: S0142-9612(22)00612-3. [Epub ahead of print]293 121972

T cell-responsive macroporous hydrogels for in situ T cell expansion and enhanced antitumor efficacy.

Rimsha Bhatta, Joonsu Han, Yusheng Liu, Yang Bo, Hua Wang.

  Adoptive T cell therapy has demonstrated great promise for treating cancer and other diseases. While extensive effort has been made to improve ex vivo expansion of T cells, strategies for maintaining the proliferation and function of T cells post adoptive transfer are still lacking. Here we report an injectable T cell-responsive macroporous hydrogel that enables in situ activation and expansion of T cells. The macroporous gel is composed of a polymeric network with dispersed macropores (∼150 μm) that are large enough to home T cells. In the presence of T cells that can gradually disrupt the gel network surrounding the macropores, activation cues can be gradually released for in situ activation and expansion of T cells. This T cell-responsive macroporous gel enables expansion of effector T cells in vivo, is stable over weeks upon subcutaneous injection, and results in enhanced CD8+ T cell response and antitumor efficacy. We further show that the T cell-responsive macroporous gel could achieve comparable antitumor efficacy to conventional T cell therapy with a much lower cell dose. This injectable, T cell-responsive macroporous gel provides a platform for in vivo expansion of engineered T cells in a controlled manner, for timely and effective treatment of diseases.

Keywords:  Cell-responsive; Hydrogel; Immunotherapy; T cell expansion; T cell therapy

DOI:  https://doi.org/10.1016/j.biomaterials.2022.121972
J Biol Chem. 2022 Dec 26. pii: S0021-9258(22)01286-8. [Epub ahead of print] 102843

TGF-β1 suppresses the T-cell response in teleost fish by initiating Smad3- and Foxp3-mediated transcriptional networks.

Qian Zhang, Ming Geng, Kang Li, Haiyou Gao, Xinying Jiao, Kete Ai, Xiumei Wei, Jialong Yang.

Transforming growth factor-β1 (TGF-β1) can suppress the activation, proliferation, and function of many T-cell subsets, protecting organisms from inflammatory and autoimmune disease caused by an overexuberant immune response. However, whether and how TGF-β1 regulates T-cell immunity in early vertebrates remain unknown. Here, using a Nile tilapia (Oreochromis niloticus) model, we investigated suppression of the T-cell response by TGF-β1 in teleost species. Tilapia encodes an evolutionarily conserved TGF-β1, the expression of which in lymphocytes is significantly induced during the immune response following Edwardsiella piscicida infection. Once activated, tilapia T cells increase TGF-β1 production, which in turn suppresses proinflammatory cytokine expression and inhibits T-cell activation. Notably, we found administration of TGF-β1 cripples the proliferation of tilapia T cells, reduces the potential capacity of Th1/2 differentiation, and impairs the cytotoxic function, rendering the fish more vulnerable to bacterial infection. Mechanistically, TGF-β1 initiates the TGF-βR/Smad signaling pathway, and triggers the phosphorylation and nuclear translocation of Smad2/3. Smad3 subsequently interacts with several transcriptional partners to repress transcription of cytokines IL-2 and IFN-γ, but promote transcription of immune checkpoint regulator CTLA4 and transcription factor Foxp3. Furthermore, TGF-β1/Smad signaling further utilizes Foxp3 to achieve the cascade regulation of these T-cell genes. Taken together, our findings reveal a detailed mechanism by which TGF-β1 suppresses the T cell-based immunity in Nile tilapia, and support the notion that TGF-β1 had already been employed to inhibit the T-cell response early in vertebrate evolution, thus providing novel insights into the evolution of the adaptive immune system.

DOI: https://doi.org/10.1016/j.jbc.2022.102843
Geroscience. 2022 Dec 29.

Altered T cell infiltration and enrichment of leukocyte regulating pathways within aged skeletal muscle are associated impaired muscle function following influenza infection.

Spencer R Keilich, Andreia N Cadar, Darcy T Ahern, Blake L Torrance, Erica C Lorenzo, Dominique E Martin, Laura Haynes, Jenna M Bartley.

  Older adults have diminished immune responses that increase susceptibility to infectious diseases, such as influenza (flu). In older adults, flu infection can lead to hospitalization, catastrophic disability, and mortality. We previously demonstrated severe and prolonged muscle degradation and atrophy in aged mice during flu infection. Here, we utilized an unbiased transcriptomic analysis to elucidate mechanisms of flu-induced muscular declines in a mouse model. Our results showed age-related gene expression differences including downregulation of genes associated with muscle regeneration and organization and upregulation of genes associated with pro-inflammatory cytokines and migratory immune pathways in aged mice when compared to young. Pathway analysis revealed significant enrichment of leukocyte migration and T cell activation pathways in the aged muscle during infection. Intramuscular CD4 T cells increased in both young and aged mice during infection, while intramuscular CD8 T cells increased exclusively in aged muscle. CD4 T cells in young muscle were regulatory T cells (Treg), while those in aged were T follicular helper (Tfh) and Th2 cells. Correspondingly, IL-33, an important cytokine for Treg accumulation within tissue, increased only in young flu-infected muscle. Conversely, CXCL10 (IP-10) increased only in aged muscle suggesting a continued recruitment of CD8 T cells into the aged muscle during flu infection. Overall, our findings elucidate a link between flu-induced disability and dysregulated intracellular T cell recruitment into flu-injured muscle with aging. Furthermore, we uncovered potential pathways involved that can be targeted to develop preventative and therapeutic interventions to avert disability and maintain independence following infection.

Keywords:  Aging; Influenza; Muscle; T cells

DOI:  https://doi.org/10.1007/s11357-022-00715-z
Immunity. 2022 Dec 19. pii: S1074-7613(22)00605-7. [Epub ahead of print]

The ectonucleotidase CD39 identifies tumor-reactive CD8+ T cells predictive of immune checkpoint blockade efficacy in human lung cancer.

Andrew Chow, Fathema Z Uddin, Michael Liu, Anton Dobrin, Barzin Y Nabet, Levi Mangarin, Yonit Lavin, Hira Rizvi, Sam E Tischfield, Alvaro Quintanal-Villalonga, Joseph M Chan, Nisargbhai Shah, Viola Allaj, Parvathy Manoj, Marissa Mattar, Maximiliano Meneses, Rebecca Landau, Mariana Ward, Amanda Kulick, Charlene Kwong, Matthew Wierzbicki, Jessica Yavner, Jacklynn Egger, Shweta S Chavan, Abigail Farillas, Aliya Holland, Harsha Sridhar, Metamia Ciampricotti, Daniel Hirschhorn, Xiangnan Guan, Allison L Richards, Glenn Heller, Jorge Mansilla-Soto, Michel Sadelain, Christopher A Klebanoff, Matthew D Hellmann, Triparna Sen, Elisa de Stanchina, Jedd D Wolchok, Taha Merghoub, Charles M Rudin.

  Improved identification of anti-tumor T cells is needed to advance cancer immunotherapies. CD39 expression is a promising surrogate of tumor-reactive CD8+ T cells. Here, we comprehensively profiled CD39 expression in human lung cancer. CD39 expression enriched for CD8+ T cells with features of exhaustion, tumor reactivity, and clonal expansion. Flow cytometry of 440 lung cancer biospecimens revealed weak association between CD39+ CD8+ T cells and tumoral features, such as programmed death-ligand 1 (PD-L1), tumor mutation burden, and driver mutations. Immune checkpoint blockade (ICB), but not cytotoxic chemotherapy, increased intratumoral CD39+ CD8+ T cells. Higher baseline frequency of CD39+ CD8+ T cells conferred improved clinical outcomes from ICB therapy. Furthermore, a gene signature of CD39+ CD8+ T cells predicted benefit from ICB, but not chemotherapy, in a phase III clinical trial of non-small cell lung cancer. These findings highlight CD39 as a proxy of tumor-reactive CD8+ T cells in human lung cancer.

Keywords:  CD8(+) T cells; T cell receptors; immune checkpoint blockade; non-small cell lung cancer; tumor mutation burden

DOI:  https://doi.org/10.1016/j.immuni.2022.12.001
Autophagy. 2022 Dec 26. 1-2

Mitochondria and peroxisomes: partners in autophagy.

Léa P Wilhelm, Ian G Ganley.

  Mitochondria, often called "the powerhouse" of the cell due to their role as the main energy supplier, regulate numerous complex processes including intracellular calcium homeostasis, reactive oxygen species (ROS) production, regulation of immune responses, and apoptosis. So, mitochondria are a fundamental metabolic hub that also control cell survival and cell death. However, they are not unique in all these functions. Indeed, peroxisomes are small cytoplasmic organelles that also ensure metabolic functions such as fatty acid oxidation and ROS production. This common relationship also extends beyond function as peroxisomes themselves can form from mitochondrial-derived precursors. Given this interconnection between mitochondria and peroxisomes involving biogenesis and function, in our recent work we determined if their turnover was also linked.

Keywords:  Autophagy; BNIP3L; NIX; mitophagy; pexophagy

DOI:  https://doi.org/10.1080/15548627.2022.2155368
Autophagy. 2022 Dec 29. 1-2

AutophagosOMES: identification of autophagosomal cargo in CD4+ T cells by proteomics.

Faris Jafri, Megan Moore, Shree Padma Metur, Daniel J Klionsky.

  Macroautophagy/autophagy, a cellular process that sequesters and breaks down cellular components in the lysosome/vacuole, is important in various events where cell composition undergoes changes. Broadly, autophagy is involved in T cell regulation including maintaining cell homeostasis. One process where a cell alters its composition is in the activation of helper T cells in the immune system. When helper (CD4+) T cells are activated by antigens, they both grow and alter their cellular components to become effector T cells. Autophagy is the process that facilitates the breakdown of these cellular components and is therefore hypothesized to have a role in CD4+ T cell activation. Previous research has concluded that CD4+ T cell activation induces autophagy, providing an avenue for further research aimed at examining the ways in which this induced autophagy affects CD4+ T cell proliferation and function. Toward this end, Zhou et al. researched the autophagosomal cargo present within CD4+ T cells and the impact this cargo has on CD4+ T cell proliferation.

Keywords:  Autophagy; T cells; cargo; mass spectrometry; proliferation; purification

DOI:  https://doi.org/10.1080/15548627.2022.2161154
Cell Metab. 2022 Dec 21. pii: S1550-4131(22)00542-3. [Epub ahead of print]

Metabolic adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments.

Ya-Ting Wang, Alissa J Trzeciak, Waleska Saitz Rojas, Pedro Saavedra, Yan-Ting Chen, Rachel Chirayil, Jon Iker Etchegaray, Christopher D Lucas, Daniel J Puleston, Kayvan R Keshari, Justin S A Perry.

  Apoptotic cell (AC) clearance (efferocytosis) is performed by phagocytes, such as macrophages, that inhabit harsh physiological environments. Here, we find that macrophages display enhanced efferocytosis under prolonged (chronic) physiological hypoxia, characterized by increased internalization and accelerated degradation of ACs. Transcriptional and translational analyses revealed that chronic physiological hypoxia induces two distinct but complimentary states. The first, "primed" state, consists of concomitant transcription and translation of metabolic programs in AC-naive macrophages that persist during efferocytosis. The second, "poised" state, consists of transcription, but not translation, of phagocyte function programs in AC-naive macrophages that are translated during efferocytosis. Mechanistically, macrophages efficiently flux glucose into a noncanonical pentose phosphate pathway (PPP) loop to enhance NADPH production. PPP-derived NADPH directly supports enhanced efferocytosis under physiological hypoxia by ensuring phagolysosomal maturation and redox homeostasis. Thus, macrophages residing under physiological hypoxia adopt states that support cell fitness and ensure performance of essential homeostatic functions rapidly and safely.

Keywords:  apoptotic cell clearance; cellular adaptation; efferocytosis; homeostasis; metabolism; oxygen; pentose phosphate pathway; physiological hypoxia

DOI:  https://doi.org/10.1016/j.cmet.2022.12.005
Arthritis Rheumatol. 2022 Dec 27.

Modulating T-bet-promoted energy metabolism in pathogenic age/autoimmune-associated B cells ameliorates lupus autoimmunity.

Xiaxia Han, Shuangshuang Gu, Soon-Min Hong, Yang Jiang, Jinsong Zhang, Chao Yao, Zhihua Yin, Zhizhong Ye, Huihua Ding, Sheng Chen, Dai Dai, Nan Shen.

OBJECTIVE: Emerging evidences indicate that a distinct CD11c+ T-bet+ B cell subset termed age/autoimmune-associated B cells (ABCs) is the major pathogenic autoantibody producer in lupus. Human lupus is associated with significant metabolic alterations, but how ABCs orchestrate their typical transcription factors (TFs) and metabolic programs to meet specific functional requirements is unclear. Our goal is to characterize the metabolism of ABCs and identify the regulators of metabolic pathways for developing new therapies for ABC-mediated autoimmunity.
METHODS: We developed a T-bet-tdTomato reporter mouse strain to trace live T-bet+ B cells and adoptively transferred CD4+ T cells from Bm12 mice to induce lupus. Then CD11c+ tdTomato+ B cells were sorted and conducted RNA sequencing and extracellular flux assay. Metabolic restriction to constrain ABC formation was tested on human and mouse B cells. The metabolic intervention was conducted in the Bm12-induced lupus model.
RESULTS: ABCs exhibited a hypermetabolic state with enhanced glycolytic capacity. The increased glycolytic rate in ABCs was promoted by IFN-γ signaling. T-bet, a downstream TF of IFN-γ, regulated the gene program of the glycolysis pathway in ABCs by repressing the expression of Bcl6. Functionally, glycolysis restriction could impair ABC formation. The engagement of glycolysis promoted survival and terminal differentiation of antibody-secreting cells. Administration of glycolysis inhibitor ameliorated ABCs accumulation and autoantibody production in Bm12-induced lupus model.
CONCLUSION: T-bet can couple immune signals and metabolic programming to establish pathogenic ABC formation and functional capacities. Modulating ABC favored metabolic program could be a novel therapeutic approach for lupus. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/art.42433
Immunity. 2022 Dec 21. pii: S1074-7613(22)00606-9. [Epub ahead of print]

CD8+ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor.

Nataliya Prokhnevska, Maria A Cardenas, Rajesh M Valanparambil, Ewelina Sobierajska, Benjamin G Barwick, Caroline Jansen, Adriana Reyes Moon, Petra Gregorova, Luke delBalzo, Rachel Greenwald, Mehmet Asim Bilen, Mehrdad Alemozaffar, Shreyas Joshi, Cara Cimmino, Christian Larsen, Viraj Master, Martin Sanda, Haydn Kissick.

  Improvements in tumor immunotherapies depend on better understanding of the anti-tumor T cell response. By studying human tumor-draining lymph nodes (TDLNs), we found that activated CD8+ T cells in TDLNs shared functional, transcriptional, and epigenetic traits with TCF1+ stem-like cells in the tumor. The phenotype and TCR overlap suggested that these TDLN cells were precursors to tumor-resident stem-like CD8+ T cells. Murine tumor models revealed that tumor-specific CD8+ T cells were activated in TDLNs but lacked an effector phenotype. These stem-like cells migrated into the tumor, where additional co-stimulation from antigen-presenting cells drove effector differentiation. This model of CD8+ T cell activation in response to cancer is different from that of canonical CD8+ T cell activation to acute viruses, and it proposes two stages of tumor-specific CD8+ T cell activation: initial activation in TDLNs and subsequent effector program acquisition within the tumor after additional co-stimulation.

Keywords:  CD8 T cells; T cell differentiation; T cell exhaustion; antigen-presenting cells; cancer; co-stimulation; tumor-draining lymph nodes; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.immuni.2022.12.002