bims-imseme 2024-02-04 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2024‒02‒04
seven papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Id2 epigenetically controls CD8+ T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex.
BATF and BATF3 deficiency alters CD8+ effector/exhausted T cells balance in skin transplantation.
Cell-intrinsic PD-L1 ablation sustains effector CD8+ T cell responses and promotes antitumor T cell therapy.
Mitochondrial dynamics and metabolic regulation control T cell fate in the thymus.
CXCL12-CXCR4 mediates CD57+ CD8+ T cell responses in the progression of type 1 diabetes.
Inhibition of CD38 enzymatic activity enhances CAR-T cell immune-therapeutic efficacy by repressing glycolytic metabolism.
NAD in pathological cardiac remodeling: Metabolic regulation and beyond.

Cell Mol Immunol. 2024 Jan 29.

Id2 epigenetically controls CD8+ T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex.

Yiming Li, Mingwei Han, Haolin Wei, Wan Huang, Zhinan Chen, Tianjiao Zhang, Meirui Qian, Lin Jing, Gang Nan, Xiuxuan Sun, Shuhui Dai, Kun Wang, Jianli Jiang, Ping Zhu, Liang Chen.

  CD8+ T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6+ progenitor exhausted (Texprog) and Tim-3+ terminally exhausted (Texterm) subpopulations. Inhibitor of DNA binding protein 2 (Id2) has been shown to play important roles in T-cell development and CD8+ T-cell immunity. However, the role of Id2 in CD8+ T-cell exhaustion is unclear. Here, we found that Id2 transcriptionally and epigenetically regulates the generation of Texprog cells and their conversion to Texterm cells. Genetic deletion of Id2 dampens CD8+ T-cell-mediated immune responses and the maintenance of stem-like CD8+ T-cell subpopulations, suppresses PD-1 blockade and increases tumor susceptibility. Mechanistically, through its HLH domain, Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex, and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase LSD1. Therefore, Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter, modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+ Texprog cells. An LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing mice. Inhibition of LSD1 increases the abundance of Slamf6+Tim-3- Texprog cells in tumors and the expression level of Tcf1 in Id2-deleted CD8+ T cells. This study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8+ T-cell exhaustion, and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.

Keywords:  Epigenetic modification; Id2; Immune evasion; T-cell exhaustion

DOI:  https://doi.org/10.1038/s41423-023-01118-6
Mol Med. 2024 Jan 31. 30(1): 16

BATF and BATF3 deficiency alters CD8+ effector/exhausted T cells balance in skin transplantation.

Chenghao Li, Zongtao Liu, Zihao Wang, Wai Yen Yim, Yajun Huang, Yuqi Chen.

  BACKGROUND: It is well-established that CD8+ T-cells play a critical role in graft rejection. The basic leucine zipper ATF-like transcription factor (BATF) and BATF3 are transcriptional factors expressed in T lymphocytes. Herein, we investigated the functions of BATF and BATF3 in the differentiation and exhaustion of CD8+ T cells following alloantigen activation.METHODS: Wild-type CD8+ T cells, BATF-deficient (Batf-/-) CD8+ T cells, and CD8+ T cells deficient in both BATF and BATF3 (Batf-/-Batf3-/-) were transferred to B6.Rag1-/- mice, which received skin allografts from BALB/c mice. Flow cytometry was conducted to investigate the number of CD8+ T cells and the percentage of effector subsets.
RESULTS: BATF expression positively correlated with effector CD8+ T cell differentiation. BATF and BATF3 deficiency promoted skin allograft long-term survival and attenuated the CD8+ T cell allo-response and cytokine secretion. Finally, BATF and BATF3 deficiency prompted the generation of exhausted CD8+ T cells.
CONCLUSIONS: Overall, our findings provide preliminary evidence that both BATF and BATF3 deficiency influences the differentiation of effector CD8+ T cells and mediates the exhaustion of CD8+ T cells, prolonging transplant survival. Targeting BATF and BATF3 to inhibit CD8+ T cell function has huge prospects for application as a therapeutic approach to prevent transplant rejection.

Keywords:  BATF; CD8+ T-cells; Graft rejection; transcription factors

DOI:  https://doi.org/10.1186/s10020-024-00792-0
Cell Rep. 2024 Jan 30. pii: S2211-1247(24)00040-8. [Epub ahead of print]43(2): 113712

Cell-intrinsic PD-L1 ablation sustains effector CD8+ T cell responses and promotes antitumor T cell therapy.

Xinran Wang, Lu Lu, Xiaochuan Hong, Lingling Wu, Chao Yang, You Wang, Wenwen Li, Yuanqin Yang, Dongqing Cao, Wen Di, Liufu Deng.

  Adoptive cell therapies are emerging forms of immunotherapy that reprogram T cells for enhanced antitumor responses. Although surface programmed cell death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) engagement inhibits antitumor immunity, the role of cell-intrinsic PD-L1 in adoptive T cell therapy remains unknown. Here, we found that intracellular PD-L1 was enriched in tumor-infiltrating CD8+ T cells of cancer patients. PD-L1 ablation promoted antitumor immune responses and the maintenance of an effector-like state of therapeutic CD8+ T cells, while blockade of surface PD-L1 was unable to impact on their expansion and function. Moreover, cell-intrinsic PD-L1 impeded CD8+ T cell activity, which partially relied on mTORC1 signaling. Furthermore, endogenous tumor-reactive CD8+ T cells were motivated by BATF3-driven dendritic cells after adoptive transfer of PD-L1-deficient therapeutic CD8+ T cells. This role of cell-intrinsic PD-L1 in therapeutic CD8+ T cell dysfunction highlights that disrupting cell-intrinsic PD-L1 in CD8+ T cells represents a viable approach to improving T cell-based cancer immunotherapy.

Keywords:  CD8(+) T cell differentiation; CP: Cancer; CP: Immunology; PD-L1/PD-1; adoptive T cell therapy; tumor immunity

DOI:  https://doi.org/10.1016/j.celrep.2024.113712
Front Immunol. 2023 ;14 1270268

Mitochondrial dynamics and metabolic regulation control T cell fate in the thymus.

Rima Elhage, Mairead Kelly, Nicolas Goudin, Jérôme Megret, Agnès Legrand, Ivan Nemazanyy, Cécilia Patitucci, Véronique Quellec, Timothy Wai, Ahmed Hamaï, Sophie Ezine.

  Several studies demonstrated that mitochondrial dynamics and metabolic pathways control T cell fate in the periphery. However, little is known about their implication in thymocyte development. Our results showed that thymic progenitors (CD3-CD4-CD8- triple negative, TN), in active division, have essentially a fused mitochondrial morphology and rely on high glycolysis and mitochondrial oxidative phosphorylation (OXPHOS). As TN cells differentiate to double positive (DP, CD4+CD8+) and single positive (SP, CD4+ and CD8+) stages, they became more quiescent, their mitochondria fragment and they downregulate glycolysis and OXPHOS. Accordingly, in vitro inhibition of the mitochondrial fission during progenitor differentiation on OP9-DL4 stroma, affected the TN to DP thymocyte transition by enhancing the percentage of TN and reducing that of DP, leading to a decrease in the total number of thymic cells including SP T cells. We demonstrated that the stage 3 triple negative pre-T (TN3) and the stage 4 triple negative pre-T (TN4) have different metabolic and functional behaviors. While their mitochondrial morphologies are both essentially fused, the LC-MS based analysis of their metabolome showed that they are distinct: TN3 rely more on OXPHOS whereas TN4 are more glycolytic. In line with this, TN4 display an increased Hexokinase II expression in comparison to TN3, associated with high proliferation and glycolysis. The in vivo inhibition of glycolysis using 2-deoxyglucose (2-DG) and the absence of IL-7 signaling, led to a decline in glucose metabolism and mitochondrial membrane potential. In addition, the glucose/IL-7R connection affects the TN3 to TN4 transition (also called β-selection transition), by enhancing the percentage of TN3, leading to a decrease in the total number of thymocytes. Thus, we identified additional components, essential during β-selection transition and playing a major role in thymic development.

Keywords:  OxPhos; T cell progenitors; glycolysis; metabolome; mitochondrial dynamics; thymus; β-selection checkpoint

DOI:  https://doi.org/10.3389/fimmu.2023.1270268
J Autoimmun. 2024 Jan 31. pii: S0896-8411(24)00005-2. [Epub ahead of print]143 103171

CXCL12-CXCR4 mediates CD57+ CD8+ T cell responses in the progression of type 1 diabetes.

Ting Zhong, Xinyu Li, Kang Lei, Rong Tang, Zhiguang Zhou, Bin Zhao, Xia Li.

  CD57+ CD8+ T cells, also referred as effector memory cells, are implicated in various conditions including tumor immunity, virus immunity, and most recently with autoimmunity. However, their roles in the progression and remission of T1D are still unclear. Here, we noted an increase in peripheral CD57+ CD8+ T cells in a T1D patient harboring an activator of transcription 3 (STAT3) mutation. Our in-depth study on the role of CD57+ CD8+ T cells within a T1D patient cohort revealed that these cells undergo significant compositional shifts during the disease's progression. Longitudinal cohort data suggested that CD57+ CD8+ T cell prevalence may be a harbinger of β-cell function decline in T1D patients. Characterized by robust cytotoxic activity, heightened production of pro-inflammatory cytokines, and increased intracellular glucose uptake, these cells may be key players in the pathophysiology of T1D. Moreover, in vitro assays showed that the CXCL12-CXCR4 axis promotes the expansion and function of CD57+ CD8+ T cells via Erk1/2 signaling. Notably, the changes of serum CXCL12 concentrations were also found in individuals during the peri-remission phase of T1D. Furthermore, treatment with the CXCR4 antagonist LY2510924 reduced the immunological infiltration of CD57+ CD8+ T cells and mitigated hyperglycemia in a STZ-induced T1D mouse model. Taken together, our work has uncovered a novel role of the CXCL12-CXCR4 axis in driving CD57+ CD8+ T cells responses in T1D, and presented a promising therapeutic strategy for delaying the onset and progression of diabetes.

Keywords:  CD57(+) CD8(+) T cells; CXCL12; Immune modulation; T cells; Type 1 diabetes

DOI:  https://doi.org/10.1016/j.jaut.2024.103171
Cell Rep Med. 2024 Jan 30. pii: S2666-3791(24)00009-0. [Epub ahead of print] 101400

Inhibition of CD38 enzymatic activity enhances CAR-T cell immune-therapeutic efficacy by repressing glycolytic metabolism.

Yue Huang, Mi Shao, Xinyi Teng, Xiaohui Si, Longyuan Wu, Penglei Jiang, Lianxuan Liu, Bohan Cai, Xiujian Wang, Yingli Han, Youqin Feng, Kai Liu, Zhaoru Zhang, Jiazhen Cui, Mingming Zhang, Yongxian Hu, Pengxu Qian, He Huang.

  Chimeric antigen receptor (CAR)-T therapy has shown superior efficacy against hematopoietic malignancies. However, many patients failed to achieve sustainable tumor control partially due to CAR-T cell exhaustion and limited persistence. In this study, by performing single-cell multi-omics data analysis on patient-derived CAR-T cells, we identify CD38 as a potential hallmark of exhausted CAR-T cells, which is positively correlated with exhaustion-related transcription factors and further confirmed with in vitro exhaustion models. Moreover, inhibiting CD38 activity reverses tonic signaling- or tumor antigen-induced exhaustion independent of single-chain variable fragment design or costimulatory domain, resulting in improved CAR-T cell cytotoxicity and antitumor response. Mechanistically, CD38 inhibition synergizes the downregulation of CD38-cADPR -Ca2+ signaling and activation of the CD38-NAD+-SIRT1 axis to suppress glycolysis. Collectively, our findings shed light on the role of CD38 in CAR-T cell exhaustion and suggest potential clinical applications of CD38 inhibition in enhancing the efficacy and persistence of CAR-T cell therapy.

Keywords:  CAR-T; CD38; SIRT1; cADPR; chimeric antigen receptor T; exhaustion; glycolysis

DOI:  https://doi.org/10.1016/j.xcrm.2024.101400
Biochim Biophys Acta Mol Basis Dis. 2024 Jan 26. pii: S0925-4439(24)00023-1. [Epub ahead of print] 167038

NAD in pathological cardiac remodeling: Metabolic regulation and beyond.

Ignacio Norambuena-Soto, Yingfeng Deng, Charles Brenner, Sergio Lavandero, Zhao V Wang.

  Nicotinamide adenine dinucleotide (NAD) coenzymes are carriers of high energy electrons in metabolism and also play critical roles in numerous signaling pathways. NAD metabolism is decreased in various cardiovascular diseases. Importantly, stimulation of NAD biosynthesis protects against heart disease under different pathological conditions. In this review, we describe pathways for both generation and catabolism of NAD coenzymes and the respective changes of these pathways in the heart under cardiac diseases, including pressure overload, myocardial infarction, cardiometabolic disease, cancer treatment cardiotoxicity, and heart failure. We next provide an update on the strategies and treatments to increase NAD levels, such as supplementation of NAD precursors, in the heart that prevent or reverse cardiomyopathy. We also introduce the approaches to manipulate NAD consumption enzymes to ameliorate cardiac disease. Finally, we discuss the mechanisms associated with improvements in cardiac function by NAD coenzymes, differentiating between mitochondria-dependent effects and those independent of mitochondrial metabolism.

Keywords:  Cardiac remodeling; Heart failure; NAD; Nicotinamide riboside

DOI:  https://doi.org/10.1016/j.bbadis.2024.167038