bims-imseme 2024-07-07 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2024–07–07
nineteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

IRF4 impedes human CD8 T cell function and promotes cell proliferation and PD-1 expression.
Inhibiting the NADase CD38 improves cytomegalovirus-specific CD8+ T cell functionality and metabolism.
Identification of Hypoxia-ALCAMhigh Macrophage- Exhausted T Cell Axis in Tumor Microenvironment Remodeling for Immunotherapy Resistance.
The dynamics and longevity of circulating CD4 + memory T cells depend on cell age and not the chronological age of the host.
Genetically engineering glycolysis in T cells increases their antitumor function.
An updated immunosenescence exploration in healthy Chinese donors: circular elevated PD-1 on T cell and increased Ki67 on CD8+ T cell towards aging.
antiCD49d Ab treatment ameliorates age-associated inflammatory response and mitigates CD8+ T-cell cytotoxicity after traumatic brain injury.
Inhibitory immune checkpoints suppress the surveillance of senescent cells promoting their accumulation with aging and in age-related diseases.
PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels.
Temporal Alterations in CD8+ T Cells During the Progression from Stage 1 to Stage 3 Type 1 Diabetes.
Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity.
Gene Regulatory Programs that Specify Age-Related Differences during Thymocyte Development.
Regulation of 3D genome organization during T cell activation.
Lrp10 suppresses IL7R limiting CD8 T cell homeostatic expansion and anti-tumor immunity.
BRD7 as key factor in PBAF complex assembly and CD8+ T cell differentiation.
Moderate-intensity aerobic exercise training improves CD8+ tumor-infiltrating lymphocytes effector function by reducing mitochondrial loss.
Sialic acids on T cells are crucial for their maintenance and survival.
SLC25A19 is required for NADH homeostasis and mitochondrial respiration.
DOK1 and DOK2 regulate CD8 T cell signaling and memory formation without affecting tumor cell killing.

Cell Rep. 2024 Jun 27. pii: S2211-1247(24)00729-0. [Epub ahead of print]43(7): 114401

IRF4 impedes human CD8 T cell function and promotes cell proliferation and PD-1 expression.

Thibault Hirsch, Damien Neyens, Céline Duhamel, Alexandre Bayard, Christophe Vanhaver, Mathieu Luyckx, Francisco Sala de Oyanguren, Claude Wildmann, Nicolas Dauguet, Jean-Luc Squifflet, Virginie Montiel, Mélanie Deschamps, Pierre van der Bruggen.

  Human CD8 tumor-infiltrating lymphocytes (TILs) with impaired effector functions and PD-1 expression are categorized as exhausted. However, the exhaustion-like features reported in TILs might stem from their activation rather than the consequence of T cell exhaustion itself. Using CRISPR-Cas9 and lentiviral overexpression in CD8 T cells from non-cancerous donors, we show that the T cell receptor (TCR)-induced transcription factor interferon regulatory factor 4 (IRF4) promotes cell proliferation and PD-1 expression and hampers effector functions and expression of nuclear factor κB (NF-κB)-regulated genes. While CD8 TILs with impaired interferon γ (IFNγ) production exhibit activation markers IRF4 and CD137 and exhaustion markers thymocyte selection associated high mobility group box (TOX) and PD-1, activated T cells in patients with COVID-19 do not demonstrate elevated levels of TOX and PD-1. These results confirm that IRF4+ TILs are exhausted rather than solely activated. Our study indicates, however, that PD-1 expression, low IFNγ production, and active cycling in TILs are all influenced by IRF4 upregulation after T cell activation.

Keywords:  CD8 T cell; CP: Immunology; IRF4; NFAT; PD-1; TILs; TOX; dysfunction; exhaustion; proliferation; tumor

DOI:  https://doi.org/10.1016/j.celrep.2024.114401
J Clin Invest. 2024 Jul 02. pii: e179561. [Epub ahead of print]

Inhibiting the NADase CD38 improves cytomegalovirus-specific CD8+ T cell functionality and metabolism.

Nils Mülling, Felix M Behr, Graham A Heieis, Kristina Boss, Suzanne van Duikeren, Floortje J van Haften, Iris N Pardieck, Esmé Ti van der Gracht, Ward Vleeshouwers, Tetje C van der Sluis, J Fréderique de Graaf, Dominique Mb Veerkamp, Kees Lmc Franken, Xin Lei, Lukas van de Sand, Sjoerd H van der Burg, Marij Jp Welters, Sebastiaan Heidt, Wesley Huisman, Simon P Jochems, Martin Giera, Oliver Witzke, Aiko Pj de Vries, Andreas Kribben, Bart Everts, Benjamin Wilde, Ramon Arens.

  Cytomegalovirus (CMV) is one of the most common and relevant opportunistic pathogens in immunocompromised individuals such as kidney transplant recipients (KTRs). The exact mechanisms underlying the disability of cytotoxic T cells to provide sufficient protection against CMV in immunosuppressed individuals have not been identified yet. Here, we performed in-depth metabolic profiling of CMV-specific CD8+ T cells in immunocompromised patients and show the development of metabolic dysregulation at the transcriptional, protein, and functional level of CMV-specific CD8+ T cells in KTRs with non-controlled CMV infection. These dysregulations comprise impaired glycolysis and increased mitochondrial stress, which is associated with an intensified expression of the nicotinamide adenine dinucleotide nucleotidase (NADase) CD38. Inhibiting NADase activity of CD38 reinvigorated the metabolism and improved cytokine production of CMV-specific CD8+ T cells. These findings were corroborated in a mouse model of CMV infection under conditions of immunosuppression. Thus, dysregulated metabolic states of CD8+ T cells could be targeted by inhibiting CD38 to reverse hypo-responsiveness in individuals who fail to control chronic viral infection.

Keywords:  Glucose metabolism; Immunology; T cells; Transplantation

DOI:  https://doi.org/10.1172/JCI179561
Adv Sci (Weinh). 2024 Jul 02. e2309885

Identification of Hypoxia-ALCAMhigh Macrophage- Exhausted T Cell Axis in Tumor Microenvironment Remodeling for Immunotherapy Resistance.

Zhenzhen Xun, Huanran Zhou, Mingyi Shen, Yao Liu, Chengcao Sun, Yanhua Du, Zhou Jiang, Liuqing Yang, Qing Zhang, Chunru Lin, Qingsong Hu, Youqiong Ye, Leng Han.

  Although hypoxia is known to be associated with immune resistance, the adaptability to hypoxia by different cell populations in the tumor microenvironment and the underlying mechanisms remain elusive. This knowledge gap has hindered the development of therapeutic strategies to overcome tumor immune resistance induced by hypoxia. Here, bulk, single-cell, and spatial transcriptomics are integrated to characterize hypoxia associated with immune escape during carcinogenesis and reveal a hypoxia-based intercellular communication hub consisting of malignant cells, ALCAMhigh macrophages, and exhausted CD8+ T cells around the tumor boundary. A hypoxic microenvironment promotes binding of HIF-1α complex is demonstrated to the ALCAM promoter therefore increasing its expression in macrophages, and the ALCAMhigh macrophages co-localize with exhausted CD8+ T cells in the tumor spatial microenvironment and promote T cell exhaustion. Preclinically, HIF-1ɑ inhibition reduces ALCAM expression in macrophages and exhausted CD8+ T cells and potentiates T cell antitumor function to enhance immunotherapy efficacy. This study reveals the systematic landscape of hypoxia at single-cell resolution and spatial architecture and highlights the effect of hypoxia on immunotherapy resistance through the ALCAMhigh macrophage-exhausted T cell axis, providing a novel immunotherapeutic strategy to overcome hypoxia-induced resistance in cancers.

Keywords:  ALCAM+ macrophage; cancer immunotherapy; exhausted T cell; hypoxia; spatial transcriptomics

DOI:  https://doi.org/10.1002/advs.202309885
bioRxiv. 2024 Jun 25. pii: 2023.10.16.562650. [Epub ahead of print]

The dynamics and longevity of circulating CD4 + memory T cells depend on cell age and not the chronological age of the host.

M Elise Bullock, Thea Hogan, Cayman Williams, Sinead Morris, Maria Nowicka, Minahil Sharjeel, Christiaan van Dorp, Andrew J Yates, Benedict Seddon.

Quantifying the kinetics with which memory T cell populations are generated and maintained is essential for identifying the determinants of the duration of immunity. The quality and persistence of circulating CD4 + effector memory (T EM ) and central memory (T CM ) T cells in mice appear to shift with age, but it is unclear whether these changes are driven by the aging host environment, by cell age effects, or both. Here we address these issues by combining DNA labelling methods, established fate-mapping systems, a novel reporter mouse strain, and mathematical models. Together, these allow us to quantify the dynamics of both young and established circulating memory CD4 + T cell subsets, within both young and old mice. We show that that these cells and their descendents become more persistent the longer they reside within the T CM and T EM pools. This behaviour may limit memory CD4 T cell diversity by skewing TCR repertoires towards clones generated early in life, but may also compensate for functional defects in new memory cells generated in old age.
Author summary: Our long-term protection against infections depends in part on the maintenance of diverse populations of memory CD4 T cells, which are made in response to the initial exposure to the pathogen or a vaccine. These cells are not long-lived, but instead are maintained dynamically at a clonal level through loss and division. Understanding how immune memory persists therefore requires measuring these rates of these processes, and how they might change with age. Here we combine experiments in mice with mathematical models to show that memory CD4 T cells exhibit complex dynamics but increase their capacity to survive as they age. This dynamic implies that as individuals age, their memory CD4 T cell populations become enriched for older clones. This established memory may compensate for functional defects in new T cell responses generated later in life.

DOI: https://doi.org/10.1101/2023.10.16.562650
J Immunother Cancer. 2024 Jul 04. pii: e008434. [Epub ahead of print]12(7):

Genetically engineering glycolysis in T cells increases their antitumor function.

Raphaëlle Toledano Zur, Orna Atar, Tilda Barliya, Shiran Hoogi, Ifat Abramovich, Eyal Gottlieb, Noga Ron-Harel, Cyrille J Cohen.

   BACKGROUND: T cells play a central role in the antitumor response. However, they often face numerous hurdles in the tumor microenvironment, including the scarcity of available essential metabolites such as glucose and amino acids. Moreover, cancer cells can monopolize these resources to thrive and proliferate by upregulating metabolite transporters and maintaining a high metabolic rate, thereby outcompeting T cells.
METHODS: Herein, we sought to improve T-cell antitumor function in the tumor vicinity by enhancing their glycolytic capacity to better compete with tumor cells. To achieve this, we engineered human T cells to express a key glycolysis enzyme, phosphofructokinase, in conjunction with Glucose transporter 3, a glucose transporter. We co-expressed these, along with tumor-specific chimeric antigen or T-cell receptors.
RESULTS: Engineered cells demonstrated an increased cytokine secretion and upregulation of T-cell activation markers compared with control cells. Moreover, they displayed superior glycolytic capacity, which translated into an improved in vivo therapeutic potential in a xenograft model of human tumors.
CONCLUSION: In summary, these findings support the implementation of T-cell metabolic engineering to enhance the efficacy of cellular immunotherapies for cancer.

Keywords:  Immunotherapy; Receptors, Antigen; T-Lymphocytes

DOI:  https://doi.org/10.1136/jitc-2023-008434
Aging (Albany NY). 2024 Jun 29. 16

An updated immunosenescence exploration in healthy Chinese donors: circular elevated PD-1 on T cell and increased Ki67 on CD8+ T cell towards aging.

Yue Chang, Wei Cao, Lianfeng Lu, Yang Han, Lin Qin, Baotong Zhou, Taisheng Li.

  Immunosenescence is a process of immune dysfunction that occurs along with aging. Many studies have focused on the changes of different lymphocyte subsets in diseases and immune aging. However, the fluctuation in the number and phenotype of lymphocyte subset caused by aging have not been comprehensively analyzed, especially the effects of new indicators such as PD-1 and Ki67 in peripheral blood have been rarely reported. We further investigated the humoral and cellular immune parameters of 150 healthy donors over 18 years old. Age was associated with decreased CD4+CD45RA+CD62L+ T cells, decreased CD4+CD45RA+CD31+ T cells, and increased memory CD4+ or CD8+ T cells, dominated by male CD8+ T cells. The loss of CD28 expression on T cells and the transverse trend of activated CD38 and HLA-DR were also related to the increased age. In addition, CD8+ T cells in men were more prominent in activation indicators, and the difference between the old and young groups was obvious. CD4+CD25+CD127- T cells percentage tended to decrease with age and did not differ significantly between gender. Interestingly, we found that age was positively associated with PD-1+ T cells and showed significant age-related variability in men. Similarly, the percentage of CD8+ki-67+ also showed an increasing trend, with significant differences between the young group and other elderly groups in males. Our findings can provide immunological clues for future aging research, offering new insights for clinical monitoring and prevention of certain diseases.

Keywords:  aging; flow cytometry; immunophenotyping; immunosenescence; lymphocyte subsets

DOI:  https://doi.org/10.18632/aging.205985
bioRxiv. 2024 Jun 22. pii: 2024.06.17.596673. [Epub ahead of print]

antiCD49d Ab treatment ameliorates age-associated inflammatory response and mitigates CD8+ T-cell cytotoxicity after traumatic brain injury.

Zhangying Chen, Kacie P Ford, Mecca B A R Islam, Hanxiao Wan, Hyebin Han, Abhirami Ramakrishnan, Ryan J Brown, Veronica Villanueva, Yidan Wang, Booker T Davis, Craig Weiss, Weiguo Cui, David Gate, Steven J Schwulst.

Patients aged 65 years and older account for an increasing proportion of patients with traumatic brain injury (TBI). Older TBI patients experience increased morbidity and mortality compared to their younger counterparts. Our prior data demonstrated that by blocking α4 integrin, anti-CD49d antibody (aCD49d Ab) abrogates CD8+ T-cell infiltration into the injured brain, improves survival, and attenuates neurocognitive deficits. Here, we aimed to uncover how aCD49d Ab treatment alters local cellular responses in the aged mouse brain. Consequently, mice incur age-associated toxic cytokine and chemokine responses long-term post-TBI. aCD49d Ab attenuates this response along with a T helper (Th)1/Th17 immunological shift and remediation of overall CD8+ T cell cytotoxicity. Furthermore, aCD49d Ab reduces CD8+ T cells exhibiting higher effector status, leading to reduced clonal expansion in aged, but not young, mouse brains with chronic TBI. Together, aCD49d Ab is a promising therapeutic strategy for treating TBI in the older people.
Graphic abstract: Aged brains after TBI comprise two pools of CD8 + T cells . The aged brain has long been resided by a population of CD8 + T cells that's exhaustive and dysfunctional. Post TBI, due to BBB impairment, functional CD8 + T cells primarily migrate into the brain parenchyma. Aged, injury-associated microglia with upregulated MHC class I molecules can present neoantigens such as neuronal and/or myelin debris in the injured brains to functional CD8+ T, resulting in downstream CD8+ T cell cytotoxicity. aCD49d Ab treatment exerts its function by blocking the migration of functional effector CD8 + T cell population, leading to less cytotoxicity and resulting in improved TBI outcomes in aged mice.

DOI: https://doi.org/10.1101/2024.06.17.596673
Biogerontology. 2024 Jul 01.

Inhibitory immune checkpoints suppress the surveillance of senescent cells promoting their accumulation with aging and in age-related diseases.

Antero Salminen.

  The accumulation of pro-inflammatory senescent cells within tissues is a common hallmark of the aging process and many age-related diseases. This modification has been called the senescence-associated secretory phenotype (SASP) and observed in cultured cells and in cells isolated from aged tissues. Currently, there is a debate whether the accumulation of senescent cells within tissues should be attributed to increased generation of senescent cells or to a defect in their elimination from aging tissues. Emerging studies have revealed that senescent cells display an increased expression of several inhibitory immune checkpoint ligands, especially those of the programmed cell death protein-1 (PD-1) ligand-1 (PD-L1) proteins. It is known that the PD-L1 ligands, especially those of cancer cells, target the PD-1 receptor of cytotoxic CD8+ T and natural killer (NK) cells disturbing their functions, e.g., evoking a decline in their cytotoxic activity and promoting their exhaustion and even apoptosis. An increase in the level of the PD-L1 protein in senescent cells was able to suppress their immune surveillance and inhibit their elimination by cytotoxic CD8+ T and NK cells. Senescent cells are known to express ligands for several inhibitory immune checkpoint receptors, i.e., PD-1, LILRB4, NKG2A, TIM-3, and SIRPα receptors. Here, I will briefly describe those pathways and examine whether these inhibitory checkpoints could be involved in the immune evasion of senescent cells with aging and age-related diseases. It seems plausible that an enhanced inhibitory checkpoint signaling can prevent the elimination of senescent cells from tissues and thus promote the aging process.

Keywords:  Ageing; Cellular senescence; Immunosenescence; Immunosuppression; Immunosurveillance; Inflammaging

DOI:  https://doi.org/10.1007/s10522-024-10114-w
Nat Metab. 2024 Jul 03.

PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels.

Qingzhang Zhu, Shiuhwei Chen, Jan-Bernd Funcke, Leon G Straub, Qian Lin, Shangang Zhao, Chanmin Joung, Zhuzhen Zhang, Dae-Seok Kim, Na Li, Christy M Gliniak, Charlotte Lee, Alberto Cebrian-Serrano, Line Pedersen, Nils Halberg, Ruth Gordillo, Christine M Kusminski, Philipp E Scherer.

PAQR4 is an orphan receptor in the PAQR family with an unknown function in metabolism. Here, we identify a critical role of PAQR4 in maintaining adipose tissue function and whole-body metabolic health. We demonstrate that expression of Paqr4 specifically in adipocytes, in an inducible and reversible fashion, leads to partial lipodystrophy, hyperglycaemia and hyperinsulinaemia, which is ameliorated by wild-type adipose tissue transplants or leptin treatment. By contrast, deletion of Paqr4 in adipocytes improves healthy adipose remodelling and glucose homoeostasis in diet-induced obesity. Mechanistically, PAQR4 regulates ceramide levels by mediating the stability of ceramide synthases (CERS2 and CERS5) and, thus, their activities. Overactivation of the PQAR4-CERS axis causes ceramide accumulation and impairs adipose tissue function through suppressing adipogenesis and triggering adipocyte de-differentiation. Blocking de novo ceramide biosynthesis rescues PAQR4-induced metabolic defects. Collectively, our findings suggest a critical function of PAQR4 in regulating cellular ceramide homoeostasis and targeting PAQR4 offers an approach for the treatment of metabolic disorders.

DOI: https://doi.org/10.1038/s42255-024-01078-9
Diabetes. 2024 Jul 05. pii: db240159. [Epub ahead of print]

Temporal Alterations in CD8+ T Cells During the Progression from Stage 1 to Stage 3 Type 1 Diabetes.

Anna-Mari Schroderus, Viola Pitkänen, Ilse Ekman, Daniella Stevens, Marja Rytkönen-Nissinen, Reeta Rintamäki, Jussi Pihlajamäki, Mikael Knip, Riitta Veijola, Jorma Toppari, Jorma Ilonen, Johanna Lempainen, Tuure Kinnunen.

CD8+ T cells are perceived to play a major role in the pathogenesis of type 1 diabetes (T1D). In this study, we characterized the function and phenotype of circulating CD8+ memory T cells in samples from individuals at different stages of T1D progression using flow cytometry and single-cell multiomics. We observed two distinct CD8+ T-cell signatures during progression of T1D within the highly differentiated CD27-CD8+ memory T cell subset. A proinflammatory signature, with an increased frequency of IFN-γ+TNF-α+ CD27-CD8+ memory T cells, was observed in children with newly diagnosed T1D (stage 3) and correlated with the level of dysglycemia at diagnosis. In contrast, a co-inhibitory signature, with an increased frequency of KLRG1+TIGIT+ CD27-CD8+ memory T cells, was observed in islet autoantibody-positive children who later progressed to T1D (stage 1). No alterations within CD27-CD8+ memory T cells were observed in adults with established T1D or in children during the initial seroconversion to islet autoantibody positivity. Single-cell multiomics analyses suggested that CD27-CD8+ T cells expressing the IFNG+TNF+ proinflammatory signature may be distinct from those expressing the KLRG1+TIGIT+ co-inhibitory signature at the single-cell level. Collectively, our findings suggest that distinct blood CD8+ T-cell signatures could be employed as potential biomarkers of T1D progression.

DOI: https://doi.org/10.2337/db24-0159
Cell Rep Med. 2024 Jun 26. pii: S2666-3791(24)00353-7. [Epub ahead of print] 101640

Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity.

Katherine Tooley, Livnat Jerby, Giulia Escobar, S Harsha Krovi, Davide Mangani, Gitanjali Dandekar, Hanning Cheng, Asaf Madi, Ella Goldschmidt, Conner Lambden, Rajesh K Krishnan, Orit Rozenblatt-Rosen, Aviv Regev, Ana C Anderson.

  CD8+ T cells must persist and function in diverse tumor microenvironments to exert their effects. Thus, understanding common underlying expression programs could better inform the next generation of immunotherapies. We apply a generalizable matrix factorization algorithm that recovers both shared and context-specific expression programs from diverse datasets to a single-cell RNA sequencing (scRNA-seq) compendium of 33,161 CD8+ T cells from 132 patients with seven human cancers. Our meta-single-cell analyses uncover a pan-cancer T cell dysfunction program that predicts clinical non-response to checkpoint blockade in melanoma and highlights CXCR6 as a pan-cancer marker of chronically activated T cells. Cxcr6 is trans-activated by AP-1 and repressed by TCF1. Using mouse models, we show that Cxcr6 deletion in CD8+ T cells increases apoptosis of PD1+TIM3+ cells, dampens CD28 signaling, and compromises tumor growth control. Our study uncovers a TCF1:CXCR6 axis that counterbalances PD1-mediated suppression of CD8+ cell responses and is essential for effective anti-tumor immunity.

Keywords:  CD28; CXCR6; T cell dysfunction; T cell exhaustion; TCF1; human; meta-analysis; pan-cancer; single cell

DOI:  https://doi.org/10.1016/j.xcrm.2024.101640
bioRxiv. 2024 Jun 17. pii: 2024.06.14.599011. [Epub ahead of print]

Gene Regulatory Programs that Specify Age-Related Differences during Thymocyte Development.

Divya Ganapathi Sankaran, Hongya Zhu, Viviana I Maymi, Isabel M Forlastro, Ya Jiang, Nathan Laniewski, Kristin M Scheible, Brian D Rudd, Andrew W Grimson.

T cell development is fundamental to immune system establishment, yet how this development changes with age remains poorly understood. Here, we construct a transcriptional and epigenetic atlas of T cell developmental programs in neonatal and adult mice, revealing the ontogeny of divergent gene regulatory programs and their link to age-related differences in phenotype and function. Specifically, we identify a gene module that diverges with age from the earliest stages of genesis and includes programs that govern effector response and cell cycle regulation. Moreover, we reveal that neonates possess more accessible chromatin during early thymocyte development, likely establishing poised gene expression programs that manifest later in thymocyte development. Finally, we leverage this atlas, employing a CRISPR-based perturbation approach coupled with single-cell RNA sequencing as a readout to uncover a conserved transcriptional regulator, Zbtb20, that contributes to age-dependent differences in T cell development. Altogether, our study defines transcriptional and epigenetic programs that regulate age-specific differences in T cell development.

DOI: https://doi.org/10.1101/2024.06.14.599011
FEBS J. 2024 Jun 29.

Regulation of 3D genome organization during T cell activation.

Bao Wang, Qian Bian.

  Within the three-dimensional (3D) nuclear space, the genome organizes into a series of orderly structures that impose important influences on gene regulation. T lymphocytes, crucial players in adaptive immune responses, undergo intricate transcriptional remodeling upon activation, leading to differentiation into specific effector and memory T cell subsets. Recent evidence suggests that T cell activation is accompanied by dynamic changes in genome architecture at multiple levels, providing a unique biological context to explore the functional relevance and molecular mechanisms of 3D genome organization. Here, we summarize recent advances that link the reorganization of genome architecture to the remodeling of transcriptional programs and conversion of cell fates during T cell activation and differentiation. We further discuss how various chromatin architecture regulators, including CCCTC-binding factor and several transcription factors, collectively modulate the genome architecture during this process.

Keywords:  3D genome organization; CTCF; TAD; T cell activation; compartment; effector T cell; loop; memory T cell; naïve T cell

DOI:  https://doi.org/10.1111/febs.17211
EMBO Rep. 2024 Jul 02.

Lrp10 suppresses IL7R limiting CD8 T cell homeostatic expansion and anti-tumor immunity.

Jamie Russell, Luming Chen, Aijie Liu, Jianhui Wang, Subarna Ghosh, Xue Zhong, Hexin Shi, Bruce Beutler, Evan Nair-Gill.

  Signals emanating from the T-cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 T-cell fate. Understanding how these signals respond to homeostatic and microenvironmental cues can reveal new ways to therapeutically direct T-cell function. Through forward genetic screening in mice, we discover that loss-of-function mutations in LDL receptor-related protein 10 (Lrp10) cause naive and central memory CD8 T cells to accumulate in peripheral lymphoid organs. Lrp10 encodes a conserved cell surface protein of unknown immunological function. T-cell activation induces Lrp10 expression, which post-translationally suppresses IL7 receptor (IL7R) levels. Accordingly, Lrp10 deletion enhances T-cell homeostatic expansion through IL7R signaling. Lrp10-deficient mice are also intrinsically resistant to syngeneic tumors. This phenotype depends on dense tumor infiltration of CD8 T cells, which display increased memory cell characteristics, reduced terminal exhaustion, and augmented responses to immune checkpoint inhibition. Here, we present Lrp10 as a new negative regulator of CD8 T-cell homeostasis and a host factor that controls tumor resistance with implications for immunotherapy.

Keywords:  Anti-tumor Immunity; CD8 T Cell; Central Memory; Homeostatic Expansion; IL7R

DOI:  https://doi.org/10.1038/s44319-024-00191-w
JCI Insight. 2024 Jul 02. pii: e171605. [Epub ahead of print]

BRD7 as key factor in PBAF complex assembly and CD8+ T cell differentiation.

Feng Huang, Yingtong Lin, Yidan Qiao, Yaochang Yuan, Zhihan Zhong, Baohong Luo, Yating Wu, Jun Liu, Jingliang Chen, Wanying Zhang, Hui Zhang, Bingfeng Liu.

  Upon infection, naïve CD8+ T cells differentiate into cytotoxic effector cells to eliminate the pathogen-infected cells. Although many mechanisms underlying this process have been demonstrated, the regulatory role of chromatin remodel system in this process remains largely unknown. Here we showed that BRD7, a component of the polybromo-associated BRG1-associated factor complex (PBAF), was required for naïve CD8+ T cells to differentiate into functional short-lived effector cells (SLECs) in response to acute infections caused by influenza virus or lymphocytic choriomeningitis virus (LCMV). BRD7-deficiency in CD8+ T cells resulted in profound defects in effector population and functions, thereby impairing viral clearance and host recovery. Further mechanical studies indicated that the expression of BRD7 significantly turned to high from naïve CD8+ T cells to effector cells, bridged BRG1 and PBRM1 to the core module of PBAF complex, consequently facilitating the assembly of PBAF complex rather than BAF complex in the effector cells. The PBAF complex changed the chromatin accessibility at the loci of Tbx21 gene and up-regulated its expression, leading to the maturation of effector T cells. Our research confirms BRD7 and the PBAF complex are key in CD8+ T cell development and present a significant target for advancing immune therapies.

Keywords:  Adaptive immunity; Immunology; Infectious disease; T cell development

DOI:  https://doi.org/10.1172/jci.insight.171605
iScience. 2024 Jun 21. 27(6): 110121

Moderate-intensity aerobic exercise training improves CD8+ tumor-infiltrating lymphocytes effector function by reducing mitochondrial loss.

Vanessa Azevedo Voltarelli, Mariane Tami Amano, Gabriel Cardial Tobias, Gabriela Silva Borges, Ailma Oliveira da Paixão, Marcelo Gomes Pereira, Niels Olsen Saraiva Câmara, Waldir Caldeira, Alberto Freitas Ribeiro, Leo Edmond Otterbein, Carlos Eduardo Negrão, James Edward Turner, Patricia Chakur Brum, Anamaria Aranha Camargo.

  Aerobic exercise training (AET) has emerged as a strategy to reduce cancer mortality, however, the mechanisms explaining AET on tumor development remain unclear. Tumors escape immune detection by generating immunosuppressive microenvironments and impaired T cell function, which is associated with T cell mitochondrial loss. AET improves mitochondrial content and function, thus we tested whether AET would modulate mitochondrial metabolism in tumor-infiltrating lymphocytes (TIL). Balb/c mice were subjected to a treadmill AET protocol prior to CT26 colon carcinoma cells injection and until tumor harvest. Tissue hypoxia, TIL infiltration and effector function, and mitochondrial content, morphology and function were evaluated. AET reduced tumor growth, improved survival, and decreased tumor hypoxia. An increased CD8+ TIL infiltration, IFN-γ and ATP production promoted by AET was correlated with reduced mitochondrial loss in these cells. Collectively, AET decreases tumor growth partially by increasing CD8+ TIL effector function through an improvement in their mitochondrial content and function.

Keywords:  Biochemistry; Biological sciences; Cancer systems biology; Immunology; Natural sciences; Physiology; Systems biology

DOI:  https://doi.org/10.1016/j.isci.2024.110121
Front Immunol. 2024 ;15 1359494

Sialic acids on T cells are crucial for their maintenance and survival.

Michael Schmidt, Alexandra T Linder, Marina Korn, Nick Schellenberg, Sarah J Meyer, Falk Nimmerjahn, Anja Werner, Markus Abeln, Rita Gerardy-Schahn, Anja K Münster-Kühnel, Lars Nitschke.

  Sialic acids are found as terminal sugars on glycan structures on cellular surfaces. T cells carry these sialoglycans abundantly, and they are thought to serve multiple functions in cell adhesion, cell migration, and protection from complement attack. We studied the role of sialoglycans on T cells in a mouse model with a T cell-specific deletion of cytidine monophosphate-sialic acid synthase (CMAS), the enzyme that is crucial for the synthesis of sialoglycans. These mice showed a T-cell deficiency in peripheral lymphoid organs. Many T cells with an undeleted Cmas allele were found in the periphery, suggesting that they escaped the Cre-mediated deletion. The remaining peripheral T cells of T cell-specific Cmas KO mice had a memory-like phenotype. Additional depletion of the complement factor C3 could not rescue the phenotype, showing that the T-cell defect was not caused by a host complement activity. Cmas-deficient T cells showed a high level of activated caspase 3, indicating an ongoing apoptosis. In bone marrow chimeric cellular transfer experiments, we observed a strong competitive disadvantage of Cmas-deficient T cells compared to wild-type T cells. These results show that sialoglycans on the surface of T cells are crucial for T-cell survival and maintenance. This function has not been recognized before and is similar to the function of sialoglycans on B cells.

Keywords:  T cell activation; T cell development; apoptosis; complement; sialic acids

DOI:  https://doi.org/10.3389/fimmu.2024.1359494
Free Radic Biol Med. 2024 Jun 27. pii: S0891-5849(24)00536-7. [Epub ahead of print]222 317-330

SLC25A19 is required for NADH homeostasis and mitochondrial respiration.

Zongsheng Jiang.

  Mitochondrial transporters facilitate the translocation of metabolites between the cytoplasm and mitochondria and are critical for mitochondrial functional integrity. Although many mitochondrial transporters are associated with metabolic diseases, how they regulate mitochondrial function and their metabolic contributions at the cellular level are largely unknown. Here, we show that mitochondrial thiamine pyrophosphate (TPP) transporter SLC25A19 is required for mitochondrial respiration. SLC25A19 deficiency leads to reduced cell viability, increased integrated stress response (ISR), enhanced glycolysis and elevated cell sensitivity to 2-deoxyglucose (2-DG) treatment. Through a series of biochemical assays, we found that the depletion of mitochondrial NADH is the primary cause of the impaired mitochondrial respiration in SLC25A19 deficient cells. We also showed involvement of SLC25A19 in regulating the enzymatic activities of complexes I and III, the tricarboxylic acid (TCA) cycle, malate-aspartate shuttle and amino acid metabolism. Consistently, addition of idebenone, an analog of coenzyme Q10, restores mitochondrial respiration and cell viability in SLC25A19 deficient cells. Together, our findings provide new insight into the functions of SLC25A19 in mitochondrial and cellular physiology, and suggest that restoring mitochondrial respiration could be a novel strategy for treating SLC25A19-associated disorders.

Keywords:  Electron transport chain; Idebenone; Mitochondrial respiration; Mitochondrial transporter; NADH; SLC25A19; TPP

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.06.019
Sci Rep. 2024 07 01. 14(1): 15053

DOK1 and DOK2 regulate CD8 T cell signaling and memory formation without affecting tumor cell killing.

Vladimir Laletin, Pierre-Louis Bernard, Camille Montersino, Yuji Yamanashi, Daniel Olive, Rémy Castellano, Geoffrey Guittard, Jacques A Nunès.

Targeting intracellular inhibiting proteins has been revealed to be a promising strategy to improve CD8+ T cell anti-tumor efficacy. Here, we are focusing on intracellular inhibiting proteins specific to TCR signaling: DOK1 and DOK2 expressed in T cells. We hypothesized that depletion of intracellular inhibition checkpoint DOK1 and DOK2 could improve CD8+ T-cell based cancer therapies. To evaluate the role of DOK1 and DOK2 depletion in physiology and effector function of CD8+ T lymphocytes and in cancer progression, we established a transgenic T cell receptor mouse model specific to melanoma antigen hgp100 (pmel-1 TCR Tg) in WT and Dok1/Dok2 DKO (double KO) mice. We showed that both DOK1 and DOK2 depletion in CD8+ T cells after an in vitro pre-stimulation induced a higher percentage of effector memory T cells as well as an up regulation of TCR signaling cascade- induced by CD3 mAbs, including the increased levels of pAKT and pERK, two major phosphoproteins involved in T cell functions. Interestingly, this improved TCR signaling was not observed in naïve CD8+ T cells. Despite this enhanced TCR signaling essentially shown upon stimulation via CD3 mAbs, pre-stimulated Dok1/Dok2 DKO CD8+ T cells did not show any increase in their activation or cytotoxic capacities against melanoma cell line expressing hgp100 in vitro. Altogether we demonstrate here a novel aspect of the negative regulation by DOK1 and DOK2 proteins in CD8+ T cells. Indeed, our results allow us to conclude that DOK1 and DOK2 have an inhibitory role following long term T cell stimulations.

DOI: https://doi.org/10.1038/s41598-024-66075-0