bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022–06–19
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Ubiquitinating the way to T cell metabolism.
  2. Fatty acid metabolism in T-cell function and differentiation.
  3. Monocarboxylate transporter 1 deficiency impacts CD8+ T lymphocytes proliferation and recruitment to adipose tissue during obesity.
  4. CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy.
  5. Voltage-gated Ca2+ channel proteins do not function as ion channels in T cells.
  6. Longitudinal analysis reveals age-related changes in the T cell receptor repertoire of human T cell subsets.
  7. Granzyme K+ CD8 T cells form a core population in inflamed human tissue.
  8. Androgen receptor-mediated CD8+ T cell stemness programs drive sex differences in antitumor immunity.
  9. Social stressors associated with age-related T lymphocyte percentages in older US adults: Evidence from the US Health and Retirement Study.
  10. Immune cell metabolism and metabolic reprogramming.
  1. J Cell Biol. 2022 Jul 04. pii: e202206006. [Epub ahead of print]221(7):
    Ubiquitinating the way to T cell metabolism.
    Sarah McPhedran, Julian J Lum.
      In this issue, Harris et al. (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202203095) show that phosphofructokinase is a substrate for ubiquitination by Fbxo7, a key protein in the ubiquitination pathway. Their findings point to a new interplay between metabolic enzyme degradation in the regulation of T cells.
    DOI:  https://doi.org/10.1083/jcb.202206006
  2. Int Immunol. 2022 Jun 14. pii: dxac025. [Epub ahead of print]
    Fatty acid metabolism in T-cell function and differentiation.
    Yusuke Endo, Toshio Kanno, Takahiro Nakajima.
      Immunometabolism has recently emerged as a field of study examining the intersection between immunology and metabolism. Studies in this area have yielded new findings on the roles of a diverse range of metabolic pathways and metabolites, which have been found to control many aspects of T-cell biology, including cell differentiation, function, and fate. A particularly important finding has been the discovery that to meet the energy requirements associated with their proliferation, activation, and specific functions, T cells switch their metabolic signatures during differentiation. For example, whereas the induction of de novo fatty acid biosynthesis and fatty acid uptake programs are required for antigen-stimulation-induced proliferation and differentiation of effector T cells, fatty acid catabolism via β-oxidation is essential for the generation of memory T cells and the differentiation of regulatory T cells. In this review, we discuss recent advances in our understanding of the metabolism in different stages of T cells and how fatty acid metabolism in these cells controls their specific functions.
    Keywords:  ACC1; fatty acid biosynthesis; immunological memory
    DOI:  https://doi.org/10.1093/intimm/dxac025
  3. iScience. 2022 Jun 17. 25(6): 104435
    Monocarboxylate transporter 1 deficiency impacts CD8+ T lymphocytes proliferation and recruitment to adipose tissue during obesity.
    C Macchi, A Moregola, M F Greco, M Svecla, F Bonacina, S Dhup, R K Dadhich, M Audano, P Sonveaux, C Mauro, N Mitro, M Ruscica, G D Norata.
      Lactate sits at the crossroad of metabolism, immunity, and inflammation. The expression of cellular lactate transporter MCT1 (known as Slc16a1) increases during immune cell activation to cope with the metabolic reprogramming. We investigated the impact of MCT1 deficiency on CD8+ T cell function during obesity-related inflammatory conditions. The absence of MCT1 impaired CD8+ T cell proliferation with a shift of ATP production to mitochondrial oxidative phosphorylation. In Slc16a1 f/f Tcell cre mice fed a high-fat diet, a reduction in the number of CD8+ T cells, which infiltrated epididymal visceral adipose tissue (epiWAT) or subcutaneous adipose tissue, was observed. Adipose tissue weight and adipocyte area were significantly reduced together with downregulation of adipogenic genes only in the epiWAT. Our findings highlight a distinct effect of MCT1 deficiency in CD8+ T cells in the crosstalk with adipocytes and reinforce the concept that targeting immunometabolic reprogramming in lymphocyte could impact the immune-adipose tissue axis in obesity.
    Keywords:  Biological sciences; Immunology; Metabolomics; Proteomics
    DOI:  https://doi.org/10.1016/j.isci.2022.104435
  4. Sci Adv. 2022 Jun 17. 8(24): eabo4271
    CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy.
    Ping-Min Chen, Eri Katsuyama, Abhigyan Satyam, Hao Li, Jose Rubio, Sungwook Jung, Sylvia Andrzejewski, J David Becherer, Maria G Tsokos, Reza Abdi, George C Tsokos.
      Infection is one of the major causes of mortality in patients with systemic lupus erythematosus (SLE). We previously found that CD38, an ectoenzyme that regulates the production of NAD+, is up-regulated in CD8+ T cells of SLE patients and correlates with the risk of infection. Here, we report that CD38 reduces CD8+ T cell function by negatively affecting mitochondrial fitness through the inhibition of multiple steps of mitophagy, a process that is critical for mitochondria quality control. Using a murine lupus model, we found that administration of a CD38 inhibitor in a CD8+ T cell-targeted manner reinvigorated their effector function, reversed the defects in autophagy and mitochondria, and improved viral clearance. We conclude that CD38 represents a target to mitigate infection rates in people with SLE.
    DOI:  https://doi.org/10.1126/sciadv.abo4271
  5. Sci Signal. 2022 Jun 14. 15(738): eabq5594
    Voltage-gated Ca2+ channel proteins do not function as ion channels in T cells.
    Michael D Cahalan.
      Calcium (Ca2+) signaling has long been known to be crucial for T cell activation. Erdogmus et al. tested the function of voltage-gated Ca2+ channel (CaV) proteins and discovered a nonchannel function mediated by an accessory subunit but found no evidence for CaV channel activity in T cells.
    DOI:  https://doi.org/10.1126/scisignal.abq5594
  6. J Clin Invest. 2022 Jun 16. pii: e158122. [Epub ahead of print]
    Longitudinal analysis reveals age-related changes in the T cell receptor repertoire of human T cell subsets.
    Xiaoping Sun, Thomas Nguyen, Achouak Achour, Annette Ko, Jeffrey Cifello, Chen Ling, Jay Sharma, Toyoko Hiroi, Yongqing Zhang, Chee W Chia, William Wood Iii, Wells W Wu, Linda Zukley, Je-Nie Phue, Kevin G Becker, Rong-Fong Shen, Luigi Ferrucci, Nan-Ping Weng.
      A diverse T cell receptor (TCR) repertoire is essential for protection against a variety of pathogens and T cell repertoire size is believed to decline with age. However, the precise size of human TCR repertoire in total and subsets of T cells, and their changes with age are not fully characterized. We conducted a longitudinal analysis of the human blood TCRα and TCRβ repertoire of CD4+ and CD8+ T cell subsets using a unique molecular identifier (UMI) based RNAseq method. Thorough analysis of 1.9 x 108 T cells yielded the lower estimate of TCR repertoire richness in an adult at 3.8 x 108. Alterations of TCR repertoire with age were observed in all four subsets of T cells. The greatest reduction was observed in naïve CD8+ T cells; the greatest clonal expansion was in memory CD8+ T cells, and the highest increased retention of TCR sequences was in memory CD8+ T cells. Our results demonstrated that age-related TCR repertoire attrition is subset specific and more profound for CD8+ than CD4+ T cells, suggesting aging has a more profound impact on the cytotoxic than on the helper T cell functions. This may explain the increased susceptibility of older adults to the novel infections.
    Keywords:  Adaptive immunity; Aging
    DOI:  https://doi.org/10.1172/JCI158122
  7. Sci Transl Med. 2022 Jun 15. 14(649): eabo0686
    Granzyme K+ CD8 T cells form a core population in inflamed human tissue.
    Accelerating Medicines Partnership RA/SLE Network
      T cell-derived pro-inflammatory cytokines are a major driver of rheumatoid arthritis (RA) pathogenesis. Although these cytokines have traditionally been attributed to CD4 T cells, we have found that CD8 T cells are notably abundant in synovium and make more interferon (IFN)-γ and nearly as much tumor necrosis factor (TNF) as their CD4 T cell counterparts. Furthermore, using unbiased high-dimensional single-cell RNA-seq and flow cytometric data, we found that the vast majority of synovial tissue and synovial fluid CD8 T cells belong to an effector CD8 T cell population characterized by high expression of granzyme K (GzmK) and low expression of granzyme B (GzmB) and perforin. Functional experiments demonstrate that these GzmK+ GzmB+ CD8 T cells are major cytokine producers with low cytotoxic potential. Using T cell receptor repertoire data, we found that CD8 GzmK+ GzmB+ T cells are clonally expanded in synovial tissues and maintain their granzyme expression and overall cell state in blood, suggesting that they are enriched in tissue but also circulate. Using GzmK and GzmB signatures, we found that GzmK-expressing CD8 T cells were also the major CD8 T cell population in the gut, kidney, and coronavirus disease 2019 (COVID-19) bronchoalveolar lavage fluid, suggesting that they form a core population of tissue-associated T cells across diseases and human tissues. We term this population tissue-enriched expressing GzmK or TteK CD8 cells. Armed to produce cytokines in response to both antigen-dependent and antigen-independent stimuli, CD8 TteK cells have the potential to drive inflammation.
    DOI:  https://doi.org/10.1126/scitranslmed.abo0686
  8. Immunity. 2022 Jun 10. pii: S1074-7613(22)00232-1. [Epub ahead of print]
    Androgen receptor-mediated CD8+ T cell stemness programs drive sex differences in antitumor immunity.
    Chao Yang, Jingsi Jin, Yuanqin Yang, Hongxiang Sun, Lingling Wu, Mingyi Shen, Xiaochuan Hong, Wenwen Li, Lu Lu, Dongqing Cao, Xinran Wang, Jing Sun, Youqiong Ye, Bing Su, Liufu Deng.
      The incidence and mortality rates of many non-reproductive human cancers are generally higher in males than in females. However, the immunological mechanism underlying sexual differences in cancers remains elusive. Here, we demonstrated that sex-related differences in tumor burden depended on adaptive immunity. Male CD8+ T cells exhibited impaired effector and stem cell-like properties compared with female CD8+ T cells. Mechanistically, androgen receptor inhibited the activity and stemness of male tumor-infiltrating CD8+ T cells by regulating epigenetic and transcriptional differentiation programs. Castration combined with anti-PD-L1 treatment synergistically restricted tumor growth in male mice. In humans, fewer male CD8+ T cells maintained a stem cell-like memory state compared with female counterparts. Moreover, AR expression correlated with tumor-infiltrating CD8+ T cell exhaustion in cancer patients. Our findings reveal sex-biased CD8+ T cell stemness programs in cancer progression and in the responses to cancer immunotherapy, providing insights into the development of sex-based immunotherapeutic strategies for cancer treatment.
    Keywords:  androgen receptor; sex differences in cancer; stem cell-like CD8(+) T cells; tumor immunity
    DOI:  https://doi.org/10.1016/j.immuni.2022.05.012
  9. Proc Natl Acad Sci U S A. 2022 Jun 21. 119(25): e2202780119
    Social stressors associated with age-related T lymphocyte percentages in older US adults: Evidence from the US Health and Retirement Study.
    Eric T Klopack, Eileen M Crimmins, Steve W Cole, Teresa E Seeman, Judith E Carroll.
      Exposure to stress is a risk factor for poor health and accelerated aging. Immune aging, including declines in naïve and increases in terminally differentiated T cells, plays a role in immune health and tissue specific aging, and may contribute to elevated risk for poor health among those who experience high psychosocial stress. Past data have been limited in estimating the contribution of life stress to the development of accelerated immune aging and investigating mediators such as lifestyle and cytomegalovirus (CMV) infection. This study utilizes a national sample of 5,744 US adults over age 50 to assess the relationship of social stress (viz., everyday discrimination, stressful life events, lifetime discrimination, life trauma, and chronic stress) with flow cytometric estimates of immune aging, including naïve and terminally differentiated T cell percentages and the ratio of CD4+ to CD8+ cells. Experiencing life trauma and chronic stress was related to a lower percentage of CD4+ naïve cells. Discrimination and chronic stress were each associated with a greater percentage of terminally differentiated CD4+ cells. Stressful life events, high lifetime discrimination, and life trauma were related to a lower percentage of CD8+ naïve cells. Stressful life events, high lifetime discrimination, and chronic stress were associated with a higher percentage of terminally differentiated CD8+ cells. High lifetime discrimination and chronic stress were related to a lower CD4+:CD8+ ratio. Lifestyle factors and CMV seropositivity partially reduced these effects. Results identify psychosocial stress as a contributor to accelerating immune aging by decreasing naïve and increasing terminally differentiated T cells.
    Keywords:  aging; immunosenescence; socioeconomic status
    DOI:  https://doi.org/10.1073/pnas.2202780119
  10. Mol Biol Rep. 2022 Jun 13.
    Immune cell metabolism and metabolic reprogramming.
    Chenchen Hu, Yuxin Xuan, Xiyang Zhang, Yang Liu, Shuya Yang, Kun Yang.
      Energy metabolism maintains the activation of intracellular and intercellular signal transduction, and plays a crucial role in immune response. Under environmental stimulation, immune cells change from resting to activation and trigger metabolic reprogramming. The immune system cells exhibit different metabolic characteristics when performing functions. The study of immune metabolism provides new insights into the function of immune cells, including how they differentiate, migrate and exert immune responses. Studies of immune cell energy metabolism are beginning to shed light on the metabolic mechanism of disease progression and reveal new ways to target inflammatory diseases such as autoimmune diseases, chronic viral infections, and cancer. Here, we discussed the relationship between immune cells and metabolism, and proposed the possibility of targeted metabolic process for disease treatment.
    Keywords:  Immune cells; Immune metabolism; Metabolic reprogramming; Targeted therapy
    DOI:  https://doi.org/10.1007/s11033-022-07474-2
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