bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021‒08‒29
sixteen papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. Front Immunol. 2021 ;12 698565
      T-cell dysfunction arising upon repeated antigen exposure prevents effective immunity and immunotherapy. Using various clinically and physiologically relevant systems, we show that a prominent feature of PD-1-expressing exhausted T cells is the development of cellular senescence features both in vivo and ex vivo. This is associated with p16INK4a expression and an impaired cell cycle G1 to S-phase transition in repeatedly stimulated T cells. We show that these T cells accumulate DNA damage and activate the p38MAPK signaling pathway, which preferentially leads to p16INK4a upregulation. However, in highly dysfunctional T cells, p38MAPK inhibition does not restore functionality despite attenuating senescence features. In contrast, p16INK4a targeting can improve T-cell functionality in exhausted CAR T cells. Collectively, this work provides insights into the development of T-cell dysfunction and identifies T-cell senescence as a potential target in immunotherapy.
    Keywords:  CAR T cells; T cells; adoptive immunotherapy; cellular senescence; exhaustion and activation markers; p16INK4a; p38MAPK
  2. Front Immunol. 2021 ;12 713704
      Elevated levels of circulating immune complexes are associated with autoimmunity and with worse prognoses in cancer. Here, we examined the effects of well-defined, soluble immune complexes (ICs) on human peripheral T cells. We demonstrate that IgG-ICs inhibit the proliferation and differentiation of a subset of naïve T cells but stimulate the division of another naïve-like T cell subset. Phenotypic analysis by multi-parameter flow cytometry and RNA-Seq were used to characterize the inhibited and stimulated T cells revealing that the inhibited subset presented immature features resembling those of recent thymic emigrants and non-activated naïve T cells, whereas the stimulated subset exhibited transcriptional features indicative of a more differentiated, early memory progenitor with a naïve-like phenotype. Furthermore, we show that while IgG1-ICs do not profoundly inhibit the proliferation of memory T cells, IgG1-ICs suppress the production of granzyme-β and perforin in cytotoxic memory T cells. Our findings reveal how ICs can link humoral immunity and T cell function.
    Keywords:  Antigen and Antibody Immune Complexes; IgG Immune Complexes (ICs); Naive and memory T cells; T cell Fc Gamma Receptors (FcgR); T cell Fc Receptors; T cell activation proliferation and inhibition; T cell antibody receptors; T cell non-canonical Fc Receptors
  3. Cancers (Basel). 2021 Aug 18. pii: 4148. [Epub ahead of print]13(16):
      Growing tumors avoid recognition and destruction by the immune system. During continuous stimulation of tumor-infiltrating lymphocytes (TILs) by tumors, TILs become functionally exhausted; thus, they become unable to kill tumor cells and to produce certain cytokines and lose their ability to proliferate. This collectively results in the immune escape of cancer cells. Here, we show that breast cancer cells expressing PD-L1 can accelerate exhaustion of persistently activated human effector CD4+ T cells, manifesting in high PD-1 and PD-L1 expression level son T cell surfaces, decreased glucose metabolism genes, strong downregulation of SWI/SNF chromatin remodeling complex subunits, and p21 cell cycle inhibitor upregulation. This results in inhibition of T cell proliferation and reduction of T cell numbers. The RNAseq analysis on exhausted CD4+ T cells indicated strong overexpression of IDO1 and genes encoding pro-inflammatory cytokines and chemokines. Some interleukins were also detected in media from CD4+ T cells co-cultured with cancer cells. The PD-L1 overexpression was also observed in CD4+ T cells after co-cultivation with other cell lines overexpressing PD-L1, which suggested the existence of a general mechanism of CD4+ T cell exhaustion induced by cancer cells. The ChIP analysis on the PD-L1 promoter region indicated that the BRM recruitment in control CD4+ T cells was replaced by BRG1 and EZH2 in CD4+ T cells strongly exhausted by cancer cells. These findings suggest that epi-drugs such as EZH2 inhibitors may be used as immunomodulators in cancer treatment.
    Keywords:  CD4+ effector T cells; PD-1; PD-L1; PD-L1/PD-1 axis; SWI/SNF complex; T cell exhaustion
  4. Cancer Discov. 2019 Oct;9(10): OF9
      A CRISPR screen in CD8+ T cells revealed genes that modulate T-cell effector functions, including Dhx37.
  5. Cancer Discov. 2019 Nov;9(11): OF5
      Ptpn2 deletion increased the ratio of TIM3+ terminally exhausted to SLAMF6+ progenitor CD8+ T cells.
  6. Cell Metab. 2021 Aug 17. pii: S1550-4131(21)00364-8. [Epub ahead of print]
      Clearance of apoptotic cells, or "efferocytosis," is essential for diverse processes including embryonic development, tissue turnover, organ regeneration, and immune cell development. The human body is estimated to remove approximately 1% of its body mass via apoptotic cell clearance daily. This poses several intriguing cell metabolism problems. For instance, phagocytes such as macrophages must induce or suppress metabolic pathways to find, engulf, and digest apoptotic cells. Then, phagocytes must manage the potentially burdensome biomass of the engulfed apoptotic cell. Finally, phagocytes reside in complex tissue architectures that vary in nutrient availability, the types of dying cells or debris that require clearance, and the neighboring cells they interact with. Here, we review advances in our understanding of these three key areas of phagocyte metabolism. We end by proposing a model of efferocytosis that integrates recent findings and establishes a new paradigm for testing how efferocytosis prevents chronic inflammatory disease and autoimmunity.
  7. Life (Basel). 2021 Aug 04. pii: 788. [Epub ahead of print]11(8):
      Epithelial ovarian cancer (EOC) is one of the most common causes of cancer-related deaths among women and is associated with age and age-related diseases. With increasing evidence of risks associated with metabolic inflammatory conditions, such as obesity and type 2 diabetes mellitus (T2DM), it is important to understand the complex pathophysiological mechanisms underlying cancer progression and metastasis. Age-related conditions can lead to both genotypic and phenotypic immune function alterations, such as induction of senescence, which can contribute to disease progression. Immune senescence is a common phenomenon in the ageing population, which is now known to play a role in multiple diseases, often detrimentally. EOC progression and metastasis, with the highest rates in the 75-79 age group in women, have been shown to be influenced by immune cells within the "milky spots" or immune clusters of the omentum. As T2DM has been reported to cause T cell senescence in both prediabetic and diabetic patients, there is a possibility that poor prognosis in EOC patients with T2DM is partly due to the accumulation of senescent T cells in the omentum. In this review, we explore this hypothesis with recent findings, potential therapeutic approaches, and future directions.
    Keywords:  T cells; diabetes mellitus; epithelial ovarian cancer; milky spots; senescence
  8. Proc Natl Acad Sci U S A. 2021 Aug 31. pii: e2107141118. [Epub ahead of print]118(35):
      Anti-PD-1 therapies can activate tumor-specific T cells to destroy tumors. However, whether and how T cells with different antigen specificity and affinity are differentially regulated by PD-1 remain vaguely understood. Upon antigen stimulation, a variety of genes is induced in T cells. Recently, we found that T cell receptor (TCR) signal strength required for the induction of genes varies across different genes and PD-1 preferentially inhibits the induction of genes that require stronger TCR signal. As each T cell has its own response characteristics, inducibility of genes likely differs across different T cells. Accordingly, the inhibitory effects of PD-1 are also expected to differ across different T cells. In the current study, we investigated whether and how factors that modulate T cell responsiveness to antigenic stimuli influence PD-1 function. By analyzing TCRs with different affinities to peptide-MHC complexes (pMHC) and pMHCs with different affinities to TCR, we demonstrated that PD-1 inhibits the expression of TCR-inducible genes efficiently when TCR:pMHC affinity is low. In contrast, affinities of peptides to MHC and MHC expression levels did not affect PD-1 sensitivity of TCR-inducible genes although they markedly altered the dose responsiveness of T cells by changing the efficiency of pMHC formation, suggesting that the strength of individual TCR signal is the key determinant of PD-1 sensitivity. Accordingly, we observed a preferential expansion of T cells with low-affinity to tumor-antigen in PD-1-deficient mice upon inoculation of tumor cells. These results demonstrate that PD-1 imposes qualitative control of T cell responses by preferentially suppressing low-affinity T cells.
    Keywords:  EC50; PD-1; T cell activation; affinity; coreceptor
  9. Cell Stem Cell. 2021 Aug 21. pii: S1934-5909(21)00296-4. [Epub ahead of print]
      The electron transport chain promotes aspartate synthesis, which is required for cancer cell proliferation. However, it is unclear whether aspartate is limiting in normal stem cells. We found that mouse hematopoietic stem cells (HSCs) depend entirely on cell-autonomous aspartate synthesis, which increases upon HSC activation. Overexpression of the glutamate/aspartate transporter, Glast, or deletion of glutamic-oxaloacetic transaminase 1 (Got1) each increased aspartate levels in HSCs/progenitor cells and increased the function of HSCs but not colony-forming progenitors. Conversely, deletion of Got2 reduced aspartate levels and the function of HSCs but not colony-forming progenitors. Deletion of Got1 and Got2 eliminated HSCs. Isotope tracing showed aspartate was used to synthesize asparagine and purines. Both contributed to increased HSC function as deletion of asparagine synthetase or treatment with 6-mercaptopurine attenuated the increased function of GLAST-overexpressing HSCs. HSC function is thus limited by aspartate, purine, and asparagine availability during hematopoietic regeneration.
    Keywords:  asparagine; aspartate; electron transport chain; hematopoietic stem cell; metabolism; mitochondria; purine; regeneration
  10. Immunology. 2021 Aug 25.
      The severity of lesions that develop in patients infected by Leishmania braziliensis is mainly associated with a highly cytotoxic and inflammatory cutaneous environment. Recently, we demonstrated that senescent T and NK cells play a role in the establishment and maintenance of this tissue inflammation. Here, we extended those findings using transcriptomic analyses that demonstrate a strong co-induction of senescence and pro-inflammatory gene signatures in cutaneous leishmaniasis (CL) lesions. The senescence-associated signature was characterized by marked expression of key genes such as ATM, Sestrin 2, p16, p21, p38. The cell type identification from deconvolution of bulk sequencing data showed that the senescence signature was linked with CD8+ effector memory and TEMRA subsets and also senescent NK cells. A key observation was that the senescence markers in the skin lesions are age-independent of patients and were correlated with lesion size. Moreover, a striking expression of the senescence-associated secretory phenotype (SASP), proinflammatory cytokine and chemokines genes were found within lesions that was most strongly associated with the senescent CD8 TEMRA subset. Collectively, our results confirm that there is a senescence transcriptomic signature in CL lesions and supports the hypothesis that lesional senescent cells have a major role in mediating immunopathology of the disease.
    Keywords:   Leishmania braziliensis ; Cutaneous leishmaniasis; immunopathogenesis; immunosenescence; senescence-associated secretory phenotype (SASP)
  11. Biol Chem. 2021 Aug 25.
      The cAMP responsive element modulator (CREM) is a transcriptional regulator of different effector cytokines in CD4+ T cells including IL-2, IL-17, IL-21 but also IL-4 and IL-13 and thus an important determinant of central T helper cell functions. Our review gives an overview over the regulation of CREM in T cells and the pleiotropic effects of CREM on CD4+ T cells in health and autoimmune diseases with a particular focus on systemic lupus erythematosus.
    Keywords:  CREMα; ICER; Th17; cAMP; interleukin 2; metabolism
  12. Nat Immunol. 2021 09;22(9): 1175-1185
      Systematic characterizations of adipose regulatory T (Treg) cell subsets and their phenotypes remain uncommon. Using single-cell ATAC-sequencing and paired single-cell RNA and T cell receptor (TCR) sequencing to map mouse adipose Treg cells, we identified CD73hiST2lo and CD73loST2hi subsets with distinct clonal expansion patterns. Analysis of TCR-sharing data implied a state transition between CD73hiST2lo and CD73loST2hi subsets. Mechanistically, we revealed that insulin signaling occurs through a HIF-1α-Med23-PPAR-γ axis to drive the transition of CD73hiST2lo into a CD73loST2hi adipose Treg cell subset. Treg cells deficient in insulin receptor, HIF-1α or Med23 have decreased PPAR-γ expression that in turn promotes accumulation of CD73hiST2lo adipose Treg cells and physiological adenosine production to activate beige fat biogenesis. We therefore unveiled a developmental trajectory of adipose Treg cells and its dependence on insulin signaling. Our findings have implications for understanding the dynamics of adipose Treg cell subsets in aged and obese contexts.
  13. Proc Natl Acad Sci U S A. 2021 Aug 31. pii: e2023909118. [Epub ahead of print]118(35):
      The trace element zinc is essential for many aspects of physiology. The mitochondrion is a major Zn2+ store, and excessive mitochondrial Zn2+ is linked to neurodegeneration. How mitochondria maintain their Zn2+ homeostasis is unknown. Here, we find that the SLC-30A9 transporter localizes on mitochondria and is required for export of Zn2+ from mitochondria in both Caenorhabditis elegans and human cells. Loss of slc-30a9 leads to elevated Zn2+ levels in mitochondria, a severely swollen mitochondrial matrix in many tissues, compromised mitochondrial metabolic function, reductive stress, and induction of the mitochondrial stress response. SLC-30A9 is also essential for organismal fertility and sperm activation in C. elegans, during which Zn2+ exits from mitochondria and acts as an activation signal. In slc-30a9-deficient neurons, misshapen mitochondria show reduced distribution in axons and dendrites, providing a potential mechanism for the Birk-Landau-Perez cerebrorenal syndrome where an SLC30A9 mutation was found.
    Keywords:  Birk–Landau–Perez cerebrorenal syndrome; SLC-30A9; Zn2+ transporters; mitochondria
  14. Cell Rep. 2021 Aug 24. pii: S2211-1247(21)01037-8. [Epub ahead of print]36(8): 109599
      Both tumors and aging alter the immune landscape of tissues. These interactions may play an important role in tumor progression among elderly patients and may suggest considerations for patient care. We leverage large-scale genomic and clinical databases to perform comprehensive comparative analysis of molecular and cellular markers of immune checkpoint blockade (ICB) response with patient age. These analyses demonstrate that aging is associated with increased tumor mutational burden, increased expression and decreased promoter methylation of immune checkpoint genes, and increased interferon gamma signaling in older patients in many cancer types studied, all of which are expected to promote ICB efficacy. Concurrently, we observe age-related alterations that might be expected to reduce ICB efficacy, such as decreases in T cell receptor diversity. Altogether, these changes suggest the capacity for robust ICB response in many older patients, which may warrant large-scale prospective study on ICB therapies among patients of advanced age.
    Keywords:  TCGA; aging; cancer; genomics; immune; immunotherapy
  15. J Immunol Res. 2021 ;2021 7483865
      Type 1 allergies, involve a complex interaction between dendritic cells and other immune cells, are pathological type 2 inflammatory immune responses against harmless allergens. Activated dendritic cells undergo extensive phenotypic and functional changes to exert their functions. The activation, differentiation, proliferation, migration, and mounting of effector reactions require metabolic reprogramming. Dendritic cells are important upstream mediators of allergic responses and are therefore an important effector of allergies. Hence, a better understanding of the underlying metabolic mechanisms of functional changes that promote allergic responses of dendritic cells could improve the prevention and treatment of allergies. Metabolic changes related to dendritic cell activation have been extensively studied. This review briefly outlines the basis of fatty acid oxidation and its association with dendritic cell immune responses. The relationship between immune metabolism and effector function of dendritic cells related to allergic diseases can better explain the induction and maintenance of allergic responses. Further investigations are warranted to improve our understanding of disease pathology and enable new treatment strategies.