bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022–06–26
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. IL-4 prevents adenosine-mediated immunoregulation by inhibiting CD39 expression.
  2. Elevated CD4+ T cell glucose metabolism in HIV+ women with diabetes mellitus.
  3. Regulation of Treg Cell Metabolism and Function in Non-Lymphoid Tissues.
  4. TCF-1 mediates chromatin intermingling during T cell development.
  5. Taming metabolic competition via glycolysis inhibition for safe and potent tumor immunotherapy.
  6. Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling.
  7. Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence.
  8. Optimal CD8+ T cell effector function requires costimulation-induced RNA-binding proteins that reprogram the transcript isoform landscape.
  9. cBAF complex components and MYC cooperate early in CD8+ T cell fate.
  10. The transcription factor RFX5 coordinates antigen-presenting function and resistance to nutrient stress in synovial macrophages.
  1. JCI Insight. 2022 Jun 22. pii: e157509. [Epub ahead of print]7(12):
    IL-4 prevents adenosine-mediated immunoregulation by inhibiting CD39 expression.
    Fengqin Fang, Wenqiang Cao, Yunmei Mu, Hirohisa Okuyama, Lingjie Li, Jingtao Qiu, Cornelia M Weyand, Jörg J Goronzy.
      The ectonucleotidase CD39 functions as a checkpoint in purinergic signaling on effector T cells. By depleting eATP and initiating the generation of adenosine, it impairs memory cell development and contributes to T cell exhaustion, thereby causing defective tumor immunity and deficient T cell responses in older adults who have increased CD39 expression. Tuning enzymatic activity of CD39 and targeting the transcriptional regulation of ENTPD1 can be used to modulate purinergic signaling. Here, we describe that STAT6 phosphorylation downstream of IL-4 signaling represses CD39 expression on activated T cells by inducing a transcription factor network including GATA3, GFI1, and YY1. GATA3 suppresses ENTPD1 transcription through prevention of RUNX3 recruitment to the ENTPD1 promoter. Conversely, pharmacological STAT6 inhibition decreases T cell effector functions via increased CD39 expression, resulting in the defective signaling of P2X receptors by ATP and stimulation of A2A receptors by adenosine. Our studies suggest that inhibiting the STAT6 pathway to increase CD39 expression has the potential to treat autoimmune disease while stimulation of the pathway could improve T cell immunity.
    Keywords:  Adaptive immunity; Aging
    DOI:  https://doi.org/10.1172/jci.insight.157509
  2. AIDS. 2022 Jun 21.
    Elevated CD4+ T cell glucose metabolism in HIV+ women with diabetes mellitus.
    Tiffany R Butterfield, David B Hanna, Robert C Kaplan, Xiaonan Xue, Jorge R Kizer, Helen G Durkin, Seble G Kassaye, Marek Nowicki, Phyllis C Tien, Elizabeth T Golub, Michelle A Floris-Moore, Kehmia Titanji, Margaret A Fischl, Sonya Heath, Clovis S Palmer, Alan L Landay, Joshua J Anzinger.
       OBJECTIVE: Immune dysfunction and chronic inflammation are characteristic of HIV infection and diabetes mellitus (DM), with CD4+ T cell metabolism implicated in the pathogenesis of each disease. However, there is limited information on CD4+ T cell metabolism in HIV+ persons with DM. We examined CD4+ T cell glucose metabolism in HIV+ women with and without DM.
    DESIGN: A case-control study was used to compare CD4+ T cell glucose metabolism in women with HIV with or without DM.
    METHODS: Non-diabetic (HIV+DM-, N = 20) or type 2 diabetic HIV+ women with (HIV+DM+, N = 16) or without (HIV+DMTx+, N = 18) anti-diabetic treatment were identified from the WIHS and matched for age, race/ethnicity, smoking status and CD4 count. CD4+ T cell immunometabolism was examined by flow cytometry, microfluidic qRT-PCR of metabolic genes, and Seahorse extracellular flux analysis of stimulated CD4+ T cells.
    RESULTS: HIV+DM+ displayed a significantly elevated proportion of CD4+ T cells expressing the immunometabolic marker GLUT1 compared to HIV+DMTx+ and HIV+DM- (p = 0.04 and p = 0.01, respectively). Relative expression of genes encoding key enzymes for glucose metabolism pathways were elevated in CD4+ T cells of HIV+DM+ compared to HIV+DMTx+ and HIV+DM-. TCR-activated CD4+ T cells from HIV+DM+ showed elevated glycolysis and oxidative phosphorylation compared to HIV+DM-.
    CONCLUSIONS: CD4+ T cells from HIV+DM+ have elevated glucose metabolism. Treatment of DM among women with HIV may partially correct CD4+ T cell metabolic dysfunction.
    DOI:  https://doi.org/10.1097/QAD.0000000000003272
  3. Front Immunol. 2022 ;13 909705
    Regulation of Treg Cell Metabolism and Function in Non-Lymphoid Tissues.
    Kai Yang.
      Regulator T cells (Tregs) play pivotal roles in maintaining immune tolerance and regulating immune responses against pathogens and tumors. Reprogramming of cellular metabolism has been determined as a crucial process that connects microenvironmental cues and signaling networks to influence homeostasis and function of tissue Tregs. In adaptation to a variety of non-lymphoid tissues, Tregs coordinate local immune signals and signaling networks to rewire cellular metabolic programs to sustain their suppressive function. Altered Treg metabolism in turn shapes Treg activation and function. In light of the advanced understanding of immunometabolism, manipulation of systemic metabolites has been emerging as an attractive strategy aiming to modulate metabolism and function of tissue Tregs and improve the treatment of immune-related diseases. In this review, we summarize key immune signals and metabolic programs involved in the regulation of tissue Tregs, review the mechanisms underlying the differentiation and function of Tregs in various non-lymphoid tissues, and discuss therapeutic intervention of metabolic modulators of tissue Tregs for the treatment of autoimmune diseases and cancer.
    Keywords:  Treg function; Treg homeostasis; Treg metabolism; metabolic signaling; tissue Treg cells
    DOI:  https://doi.org/10.3389/fimmu.2022.909705
  4. Nat Immunol. 2022 Jun 24.
    TCF-1 mediates chromatin intermingling during T cell development.
      
    DOI:  https://doi.org/10.1038/s41590-022-01237-8
  5. Biochem Pharmacol. 2022 Jun 21. pii: S0006-2952(22)00247-7. [Epub ahead of print] 115153
    Taming metabolic competition via glycolysis inhibition for safe and potent tumor immunotherapy.
    Jun Lei, Yi Yang, Zhaoliang Lu, Haiyan Pan, Jialing Fang, Baowei Jing, Yongshun Chen, Lei Yin.
      Metabolic competition between tumors and T cells is fierce in the tumor microenvironment (TME). Tumors usually exhaust glucose and accumulate lactic acid in TME. Nutrient deprivation and lactic acid accumulation in TME blunt T cell functions and antitumor immune responses. Here, we reported that glycolysis-related genes were upregulated in melanoma patients with weak immune responses and T cell poorly infiltrated tumors of BRCA and COAD patients. Dimethyl fumarate (DMF), a GAPDH inhibitor, which is FDA proved to treat autoimmune diseases was identified to promote oxidative pentose phosphate pathway through glucose-6-phosphate dehydrogenase (G6PD) but to suppress aerobic glycolysis and oxidative phosphorylation in tumor cells. Additionally, DMF normalized metabolic competition between tumors and T cells, thus potentiate antitumor responses of tumor infiltrating CD8+ T lymphocytes (TILs). Moreover, DMF optimized the efficiency of immune checkpoint therapy and interleukin-2 (IL-2) therapy while eliminating severe toxicity induced by IL-2 therapy. This study indicates a novel clinically feasible therapy strategy aiming shared metabolic pathway of tumors and T cells for effective and less toxic tumor immunotherapy.
    Keywords:  Immunotherapy; Metabolic competition; Metabolic regulation; T cell; Tumor microenvironment; Tumors
    DOI:  https://doi.org/10.1016/j.bcp.2022.115153
  6. Cell Chem Biol. 2022 Jun 09. pii: S2451-9456(22)00204-5. [Epub ahead of print]
    Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling.
    Chen-Lu Geng, Jun-Yi Chen, Tian-Yu Song, Jae Hyung Jung, Min Long, Min-Fang Song, Tong Ji, Byung Soh Min, Jin Gu Lee, Bo Peng, Yi-Sheng Pu, Hong-Jie Fan, Piliang Hao, Qi Zhou, Eui-Cheol Shin, Yong Cang.
      Programmed cell death protein 1 (PD-1) checkpoint blockade therapy requires the CD28 co-stimulatory receptor for CD8+ T cell expansion and cytotoxicity. However, CD28 expression is frequently lost in exhausted T cells and during immune senescence, limiting the clinical benefits of PD-1 immunotherapy in individuals with cancer. Here, using a cereblon knockin mouse model that regains in vivo T cell response to lenalidomide, an immunomodulatory imide drug, we show that lenalidomide reinstates the anti-tumor activity of CD28-deficient CD8+ T cells after PD-1 blockade. Lenalidomide redirects the CRL4Crbn ubiquitin ligase to degrade Ikzf1 and Ikzf3 in T cells and unleashes paracrine interleukin-2 (IL-2) and intracellular Notch signaling, which collectively bypass the CD28 requirement for activation of intratumoral CD8+ T cells and inhibition of tumor growth by PD-1 blockade. Our results suggest that PD-1 immunotherapy can benefit from a lenalidomide combination when treating solid tumors infiltrated with abundant CD28- T cells.
    Keywords:  CD28; CRBN; Notch signaling; PD-1; immunotherapy; lenalidomide
    DOI:  https://doi.org/10.1016/j.chembiol.2022.05.012
  7. Cancer Cell. 2022 Jun 17. pii: S1535-6108(22)00231-8. [Epub ahead of print]
    Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence.
    Julia A Belk, Winnie Yao, Nghi Ly, Katherine A Freitas, Yan-Ting Chen, Quanming Shi, Alfredo M Valencia, Eric Shifrut, Nupura Kale, Kathryn E Yost, Connor V Duffy, Bence Daniel, Madeline A Hwee, Zhuang Miao, Alan Ashworth, Crystal L Mackall, Alexander Marson, Julia Carnevale, Santosh A Vardhana, Ansuman T Satpathy.
      T cell exhaustion limits antitumor immunity, but the molecular determinants of this process remain poorly understood. Using a chronic stimulation assay, we performed genome-wide CRISPR-Cas9 screens to systematically discover regulators of T cell exhaustion, which identified an enrichment of epigenetic factors. In vivo CRISPR screens in murine and human tumor models demonstrated that perturbation of the INO80 and BAF chromatin remodeling complexes improved T cell persistence in tumors. In vivo Perturb-seq revealed distinct transcriptional roles of each complex and that depletion of canonical BAF complex members, including Arid1a, resulted in the maintenance of an effector program and downregulation of exhaustion-related genes in tumor-infiltrating T cells. Finally, Arid1a depletion limited the acquisition of exhaustion-associated chromatin accessibility and led to improved antitumor immunity. In summary, we provide an atlas of the genetic regulators of T cell exhaustion and demonstrate that modulation of epigenetic state can improve T cell responses in cancer immunotherapy.
    Keywords:  CRISPR; T cell exhaustion; canonical BAF complex; chromatin remodeling; epigenetics; genomics; immunology; in vivo Perturb-seq
    DOI:  https://doi.org/10.1016/j.ccell.2022.06.001
  8. Nat Commun. 2022 Jun 20. 13(1): 3540
    Optimal CD8+ T cell effector function requires costimulation-induced RNA-binding proteins that reprogram the transcript isoform landscape.
    Timofey A Karginov, Antoine Ménoret, Anthony T Vella.
      Boosting T cell activation through costimulation directs defense against cancer and viral infections. Despite multiple studies targeting costimulation in clinical trials, the increased potency and reprogramming of T cells endowed by costimulation is poorly understood. Canonical dogma states that transcription mediates T cell activation. Here, we show that the spliceosome, controlling post-transcriptional alternative splicing and alternative polyadenylation, is the most enriched pathway in T cells after CD134/CD137 costimulation. Costimulation of CD8+ T cells significantly increases expression of 29 RNA-binding proteins while RNA-seq uncovers over 1000 differential alternative splicing and polyadenylation events. Using in vivo mouse and in vitro human models, we demonstrate that RNA-binding protein Tardbp is required for effector cytokine production, CD8+ T cell clonal expansion, and isoform regulation after costimulation. The prospect of immune response optimization through reprogramming of mRNA isoform production offered herein opens new avenues for experimentally and therapeutically tuning the activities of T cells.
    DOI:  https://doi.org/10.1038/s41467-022-31228-0
  9. Nature. 2022 Jun 22.
    cBAF complex components and MYC cooperate early in CD8+ T cell fate.
    Ao Guo, Hongling Huang, Zhexin Zhu, Mark J Chen, Hao Shi, Sujing Yuan, Piyush Sharma, Jon P Connelly, Swantje Liedmann, Yogesh Dhungana, Zhenrui Li, Dalia Haydar, Mao Yang, Helen Beere, Jason T Yustein, Christopher DeRenzo, Shondra M Pruett-Miller, Jeremy Chase Crawford, Giedre Krenciute, Charles W M Roberts, Hongbo Chi, Douglas R Green.
      The identification of mechanisms to promote memory T (Tmem) cells has important implications for vaccination and anti-cancer immunotherapy1-4. Using a CRISPR-based screen for negative regulators of Tmem cell generation in vivo5, here we identify multiple components of the mammalian canonical BRG1/BRM-associated factor (cBAF)6,7. Several components of the cBAF complex are essential for the differentiation of activated CD8+ T cells into T effector (Teff) cells, and their loss promotes Tmem cell formation in vivo. During the first division of activated CD8+ T cells, cBAF and MYC8 frequently co-assort asymmetrically to the two daughter cells. Daughter cells with high MYC and high cBAF display a cell fate trajectory towards Teff cells, whereas those with low MYC and low cBAF preferentially differentiate towards Tmem cells. The cBAF complex and MYC physically interact to establish the chromatin landscape in activated CD8+ T cells. Treatment of naive CD8+ T cells with a putative cBAF inhibitor during the first 48 h of activation, before the generation of chimeric antigen receptor T (CAR-T) cells, markedly improves efficacy in a mouse solid tumour model. Our results establish cBAF as a negative determinant of Tmem cell fate and suggest that manipulation of cBAF early in T cell differentiation can improve cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-022-04849-0
  10. Nat Metab. 2022 Jun 23.
    The transcription factor RFX5 coordinates antigen-presenting function and resistance to nutrient stress in synovial macrophages.
    Zhaolan Hu, Tuantuan V Zhao, Tao Huang, Shozo Ohtsuki, Ke Jin, Isabel N Goronzy, Bowen Wu, Matthew P Abdel, Jacob W Bettencourt, Gerald J Berry, Jörg J Goronzy, Cornelia M Weyand.
      Tissue macrophages (Mϕ) are essential effector cells in rheumatoid arthritis (RA), contributing to autoimmune tissue inflammation through diverse effector functions. Their arthritogenic potential depends on their proficiency to survive in the glucose-depleted environment of the inflamed joint. Here, we identify a mechanism that links metabolic adaptation to nutrient stress with the efficacy of tissue Mϕ to activate adaptive immunity by presenting antigen to tissue-invading T cells. Specifically, Mϕ populating the rheumatoid joint produce and respond to the small cytokine CCL18, which protects against cell death induced by glucose withdrawal. Mechanistically, CCL18 induces the transcription factor RFX5 that selectively upregulates glutamate dehydrogenase 1 (GLUD1), thus enabling glutamate utilization to support energy production. In parallel, RFX5 enhances surface expression of HLA-DR molecules, promoting Mϕ-dependent expansion of antigen-specific T cells. These data place CCL18 at the top of a RFX5-GLUD1 survival pathway and couple adaptability to nutrient conditions in the tissue environment to antigen-presenting function in autoimmune tissue inflammation.
    DOI:  https://doi.org/10.1038/s42255-022-00585-x
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