bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021–10–17
seven papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. The Role of Non-essential Amino Acids in T Cell Function and Anti-tumour Immunity.
  2. Functional heterogeneity and adaptation of naive T cells in response to tonic TCR signals.
  3. A guide to senolytic intervention in neurodegenerative disease.
  4. Homeostatic cytokines tune naivety and stemness of cord blood-derived transgenic T cells.
  5. Age-related differences in T cell subsets in a nationally representative sample of people over age 55: Findings from the Health and Retirement Study.
  6. Mitochondrial translation is required for sustained killing by cytotoxic T cells.
  7. Nitro-Deficient Niclosamide Confers Reduced Genotoxicity and Retains Mitochondrial Uncoupling Activity for Cancer Therapy.
  1. Arch Immunol Ther Exp (Warsz). 2021 Oct 12. 69(1): 29
    The Role of Non-essential Amino Acids in T Cell Function and Anti-tumour Immunity.
    Helen Carrasco Hope, Robert J Salmond.
      T cell activation, differentiation and proliferation is dependent upon and intrinsically linked to a capacity to modulate and adapt cellular metabolism. Antigen-induced activation stimulates a transcriptional programme that results in metabolic reprogramming, enabling T cells to fuel anabolic metabolic pathways and provide the nutrients to sustain proliferation and effector responses. Amino acids are key nutrients for T cells and have essential roles as building blocks for protein synthesis as well as in numerous metabolic pathways. In this review, we discuss the roles for uptake and biosynthesis of non-essential amino acids in T cell metabolism, activation and effector function. Furthermore, we highlight the effects of amino acid metabolism and depletion by cancer cells on T cell anti-tumour function and discuss approaches to modulate and improve T cell metabolism for improved anti-tumour function in these nutrient-depleted microenvironments.
    Keywords:  Immunotherapy; Metabolism; Non-essential amino acid; T cell; Tumour microenvironment
    DOI:  https://doi.org/10.1007/s00005-021-00633-6
  2. Curr Opin Immunol. 2021 Oct 12. pii: S0952-7915(21)00125-4. [Epub ahead of print]73 43-49
    Functional heterogeneity and adaptation of naive T cells in response to tonic TCR signals.
    Joel Eggert, Byron B Au-Yeung.
      Mature CD4+ and CD8+ T cells constitutively experience weak T cell receptor (TCR) stimulation in response to self-antigens, termed tonic (or basal) signaling. How tonic TCR signal strength impacts T cell responses to foreign antigens is an active area of investigation. Such studies rely on surrogate markers of tonic signal strength, including CD5, Ly6C, and transgenic reporters of Nr4a genes. Recent research indicates that strong tonic TCR signal strength influences basal T cell metabolism, effector differentiation, and TCR signal transduction. T cells that experience the strongest tonic TCR signaling exhibit features of T cell activation and negative regulation. These data suggest a model whereby adaptation to tonic signaling has lasting effects that alter T cell activation and differentiation.
    DOI:  https://doi.org/10.1016/j.coi.2021.09.007
  3. Mech Ageing Dev. 2021 Oct 07. pii: S0047-6374(21)00157-3. [Epub ahead of print] 111585
    A guide to senolytic intervention in neurodegenerative disease.
    Suckwon Lee, Ellen Y Wang, Alexandra B Steinberg, Chaska C Walton, Shankar J Chinta, Julie K Andersen.
      Cellular senescence is a potential tumor-suppressive mechanism that generally results in an irreversible cell cycle arrest. Senescent cells accumulate with age and actively secrete soluble factors, collectively termed the 'senescence-associated secretory phenotype' (SASP), which has both beneficial and detrimental effects. Although the contribution of senescent cells to age-related pathologies has been well-established outside the brain, emerging evidence indicates that brain cells also undergo cellular senescence and contribute to neuronal loss in the context of age-related neurodegenerative diseases. Contribution of senescent cells in the pathogenesis of neurological disorders has led to the possibility of eliminating senescence cells via pharmacological compounds called senolytics. Recently several senolytics have been demonstrated to elicit improved cognitive performance and healthspan in mouse models of neurodegeneration. However, their translation for use in the clinic still holds several potential challenges. This review summarizes available senolytics, their purported mode of action, and possible off-target effects. We also discuss possible alternative strategies that may help minimize potential side-effects associated with the senolytics approach.
    Keywords:  Aging; Immune surveillance; Neurodegeneration; Senescence; Senescence-associated secretory phenotype; Senolytic; neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.mad.2021.111585
  4. Cancer Gene Ther. 2021 Oct 13.
    Homeostatic cytokines tune naivety and stemness of cord blood-derived transgenic T cells.
    Chrystel Marton, Patricia Mercier-Letondal, Romain Loyon, Olivier Adotévi, Christophe Borg, Jeanne Galaine, Yann Godet.
      Engineered T-cell therapies have proven to be successful in cancer and their clinical effectiveness is directly correlated with the infused T-cell differentiation profile. Indeed, stem cell memory and central memory T cells proliferate and persist longer in vivo compared with more-differentiated T cells, while conferring enhanced antitumor activity. Here, we propose an optimized process using cord blood (CB) to generate minimally differentiated T-cell products in terms of phenotype, function, gene expression, and metabolism, using peripheral blood (PB)-derived T cells cultured with IL-2 as a standard. Phenotypically, CB-derived T cells, particularly CD4 T cells, are less differentiated than their PB counterparts when cultured with IL-2 or with IL-7 and IL-15. Furthermore, culture with IL-7 and IL-15 enables better preservation of less-differentiated CB-derived T cells compared with IL-2. In addition, transcriptomic and metabolic assessments of CB-derived transgenic T cells cultured with IL-7 and IL-15 point out their naivety and stemness signature. These relatively quiescent transgenic T cells are nevertheless primed for secondary stimulation and cytokine production. In conclusion, our study indicates that CB may be used as a source of early differentiated T cells to develop more effective adoptive cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41417-021-00395-5
  5. J Gerontol A Biol Sci Med Sci. 2021 Oct 11. pii: glab300. [Epub ahead of print]
    Age-related differences in T cell subsets in a nationally representative sample of people over age 55: Findings from the Health and Retirement Study.
    Bharat Thyagarajan, Jessica Faul, Sithara Vivek, Jung Ki Kim, Janko Nikolich-Žugich, David Weir, Eileen M Crimmins.
      Though T cell immunosenescence is a major risk factor for age-related diseases, susceptibility to infections, and responses to vaccines, differences in T cells subset counts and representation by age and sex have not been determined for a large sample representative of the national population of the US. We evaluated the counts of T cell subsets including total, CD4+ and CD8+ T cells, and their naïve (Tn), effector memory (Tem) and effector subsets, in the context of age, sex and exposure to cytomegalovirus (CMV) infection among 8,848 Health and Retirement Study (HRS) participants, a nationally representative study of adults over 55 years. Total T cells (CD3+) and CD4+ cells declined markedly with age; CD8+ T cells declined somewhat less. While CD4+ T cell declines with age occurred for both CMV seropositive and CMV seronegative groups, total T cells and CD8+ cells were both substantially higher among the CMV seropositive group. Numbers of Tn CD4+ and CD8+ cells were strongly and inversely related to age, were better conserved among women, and were independent of CMV seropositivity. By contrast, accumulation of the CD8+ and CD4+ Tem and effector subsets was CMV-associated. This is the first study to provide counts of T cell subsets by age and sex in a national sample of older US adults over the age of 55 years. Understanding T cell changes with age and sex is an important first step in determining strategies to reduce its impact on age-related diseases and susceptibility to infection.
    Keywords:  Aging; CMV Seropositivity; Older adults
    DOI:  https://doi.org/10.1093/gerona/glab300
  6. Science. 2021 Oct 15. 374(6565): eabe9977
    Mitochondrial translation is required for sustained killing by cytotoxic T cells.
    Miriam Lisci, Philippa R Barton, Lyra O Randzavola, Claire Y Ma, Julia M Marchingo, Doreen A Cantrell, Vincent Paupe, Julien Prudent, Jane C Stinchcombe, Gillian M Griffiths.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/science.abe9977
  7. Int J Mol Sci. 2021 Sep 27. pii: 10420. [Epub ahead of print]22(19):
    Nitro-Deficient Niclosamide Confers Reduced Genotoxicity and Retains Mitochondrial Uncoupling Activity for Cancer Therapy.
    Tsz Wai Ngai, Gamal Ahmed Elfar, Pearlyn Yeo, Nicholas Phua, Jin Hui Hor, Shuwen Chen, Ying Swan Ho, Chit Fang Cheok.
      Niclosamide is an oral anthelmintic drug, approved for use against tapeworm infections. Recent studies suggest however that niclosamide may have broader clinical applications in cancers, spurring increased interest in the functions and mechanisms of niclosamide. Previously, we reported that niclosamide targets a metabolic vulnerability in p53-deficient tumours, providing a basis for patient stratification and personalised treatment strategies. In the present study, we functionally characterised the contribution of the aniline 4'-NO2 group on niclosamide to its cellular activities. We demonstrated that niclosamide induces genome-wide DNA damage that is mechanistically uncoupled from its antitumour effects mediated through mitochondrial uncoupling. Elimination of the nitro group in ND-Nic analogue significantly reduced γH2AX signals and DNA breaks while preserving its antitumour mechanism mediated through a calcium signalling pathway and arachidonic acid metabolism. Lipidomics profiling further revealed that ND-Nic-treated cells retained a metabolite profile characteristic of niclosamide-treated cells. Notably, quantitative scoring of drug sensitivity suggests that elimination of its nitro group enhanced the target selectivity of niclosamide against p53 deficiency. Importantly, the results also raise concern that niclosamide may impose a pleiotropic genotoxic effect, which limits its clinical efficacy and warrants further investigation into alternative drug analogues that may ameliorate any potential unwanted side effects.
    Keywords:  genotoxicity; lipidomics; mitochondrial uncoupling; niclosamide; p53
    DOI:  https://doi.org/10.3390/ijms221910420
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