bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021‒03‒07
thirteen papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. Cell Death Differ. 2021 Mar 01.
      Optic atrophy 1 (OPA1), a mitochondria-shaping protein controlling cristae biogenesis and respiration, is required for memory T cell function, but whether it affects intrathymic T cell development is unknown. Here we show that OPA1 is necessary for thymocyte maturation at the double negative (DN)3 stage when rearrangement of the T cell receptor β (Tcrβ) locus occurs. By profiling mitochondrial function at different stages of thymocyte maturation, we find that DN3 cells rely on oxidative phosphorylation. Consistently, Opa1 deletion during early T cell development impairs respiration of DN3 cells and reduces their number. Opa1-deficient DN3 cells indeed display stronger TCR signaling and are more prone to cell death. The surviving Opa1-/- thymocytes that reach the periphery as mature T cells display an effector memory phenotype even in the absence of antigenic stimulation but are unable to generate metabolically fit long-term memory T cells. Thus, mitochondrial defects early during T cell development affect mature T cell function.
  2. Cancer Lett. 2021 Mar 01. pii: S0304-3835(21)00086-0. [Epub ahead of print]
      The persistent antigen stimulation during chronic infections and cancer results in CD8+ T cell exhaustion. The exhausted T (Tex) cells within the tumor microenvironment (TME) are characterized by increased expression of multiple co-inhibitory receptors simultaneously, progressive loss of effector function, poor proliferation and self-renewal capacity, and dysregulated metabolic activity. Emerging insights into molecular mechanisms underlying T cell exhaustion have proposed potential approaches to improve the efficacy of cancer immunotherapy via restoring the effector function of Tex cells. In this review, we summarize the fundamental characteristics (e.g., inhibitory receptors and transcriptional factors) regarding Tex cell differentiation and discuss in particular how those exhaustion features are acquired and shaped by key factors within the TME. Additionally, we discuss the progress and limitations of current cancer immunotherapeutic strategies targeting Tex cells in clinical setting.
    Keywords:  Immunotherapy; Inhibitory receptors; T cell exhaustion; Transcriptional factors; Tumor microenvironment factors
  3. Life (Basel). 2021 Feb 17. pii: 153. [Epub ahead of print]11(2):
      Cellular stress responses influence cell fate decisions. Apoptosis and proliferation represent opposing reactions to cellular stress or damage and may influence distinct health outcomes. Clinical and epidemiological studies consistently report inverse comorbidities between age-associated neurodegenerative diseases and cancer. This review discusses how one particular stress response, cellular senescence, may contribute to this inverse correlation. In mitotically competent cells, senescence is favorable over uncontrolled proliferation, i.e., cancer. However, senescent cells notoriously secrete deleterious molecules that drive disease, dysfunction and degeneration in surrounding tissue. In recent years, senescent cells have emerged as unexpected mediators of neurodegenerative diseases. The present review uses pre-defined criteria to evaluate evidence of cellular senescence in mitotically competent brain cells, highlights the discovery of novel molecular regulators and discusses how this single cell fate decision impacts cancer and degeneration in the brain. We also underscore methodological considerations required to appropriately evaluate the cellular senescence stress response in the brain.
    Keywords:  Alzheimer’s disease; biology of aging; brain; cancer; cellular senescence; geroscience; neurodegeneration; senolytics; stress response; tauopathy
  4. Cold Spring Harb Perspect Biol. 2021 Mar 01. pii: a038661. [Epub ahead of print]
      The generation of effective adaptive T-cell memory is a cardinal feature of the adaptive immune system. The establishment of protective T-cell immunity requires the differentiation of CD8+ T cells from a naive state to one where pathogen-specific memory CD8+ T cells are capable of responding to a secondary infection more rapidly and robustly without the need for further differentiation. The study of factors that determine the fate of activated CD8+ T cells into either effector or memory subsets has a long history. The advent of new technologies is now providing new insights into how epigenetic regulation not only impacts acquisition and maintenance of effector function, but also the maintenance of the quiescent yet primed memory state. There is growing appreciation that rather than distinct subsets, memory T-cell populations may reflect different points on a spectrum between the starting naive T-cell population and a terminally differentiated effector CD8+ T-cell population. Interestingly, there is growing evidence that the molecular mechanisms that underpin the rapid effector function of memory T cells are also observed in innate immune cells such as macrophages and natural killer (NK) cells. This raises an interesting hypothesis that the memory/effector T-cell state represents a default innate-like response to antigen recognition, and that it is the naive state that is the defining feature of adaptive immunity. These issues are discussed.
  5. Immunol Rev. 2021 Feb 28.
      The conceptualization of adaptive immunity, founded on the observation of immunological memory, has served as the basis for modern vaccination and immunotherapy approaches. This fundamental concept has allowed immunologists to explore mechanisms that enable humoral and cellular lymphocytes to tailor immune response functions to a wide array of environmental insults and remain poised for future pathogenic encounters. Until recently, for T cells it has remained unclear how memory differentiation acquires and sustains a gene expression program that grants a cell with a capacity for a heightened recall response. Recent investigations into this critical question have identified epigenetic programs as a causal molecular mechanism governing T cell subset specification and immunological memory. Here, we outline the studies that have illustrated this concept and posit on how insights into T cell adaptive immunity can be applied to improve upon existing immunotherapies.
    Keywords:  DNA methylation; T cell differentiation; T cell exhaustion; epigenetics; histone modifications
  6. Cell Metab. 2021 Mar 02. pii: S1550-4131(21)00066-8. [Epub ahead of print]33(3): 470-472
      When T cells are exposed to continuous antigen stimulation, they become exhausted. Here, we preview findings from Scharping et al. (2021), who have illuminated the molecular mechanism by which the persistent antigen stimulation and severe hypoxic conditions in the intratumoral environment drive T cell exhaustion, losing their cytotoxic function and anticancer effects.
  7. Cancer Immunol Res. 2021 Mar;9(3): 255-260
      The success of immune-checkpoint blockade and chimeric antigen receptor (CAR) T cell therapies has established the remarkable capacity of the immune system to fight cancer. Over the past several years, it has become clear that immune cell responses to cancer are critically dependent upon metabolic programs that are specific to both immune cell type and function. Metabolic features of cancer cells and the tumor microenvironment impose constraints on immune cell metabolism that can favor immunosuppressive phenotypes and block antitumor responses. Advances in both preclinical and clinical studies have demonstrated that metabolic interventions can dramatically enhance the efficacy of immune-based therapies for cancer. As such, understanding the metabolic requirements of immune cells in the tumor microenvironment, as well as the limitations imposed therein, can have significant benefits for informing both current practice and future research in cancer immunotherapy.
  8. Front Cell Dev Biol. 2020 ;8 624380
      In aged individuals, age-related changes in immune cells, especially T cell deficiency, are associated with an increased incidence of infection, tumor, and autoimmune disease, as well as an impaired response to vaccination. However, the features of gene expression levels in aged T cells are still unknown. Our previous study successfully tracked aged T cells generated from one wave of developing thymocytes of young age by a lineage-specific and inducible Cre-controlled reporter (TCRδ CreER R26 ZsGreen mouse strain). In this study, we utilized this model and genome-wide transcriptomic analysis to examine changes in gene expression in aged naïve and memory T cell populations during the aging process. We identified profound gene alterations in aged CD4 and CD8 T cells. Both aged CD4+ and CD8+ naïve T cells showed significantly decreased organelle function. Importantly, genes associated with lymphocyte activation and function demonstrated a significant increase in aged memory T cells, accompanied by upregulation of immunosuppressive markers and immune checkpoints, revealing an abnormal T cell function in aged cells. Furthermore, aging significantly affects T cell survival and death signaling. While aged CD4 memory T cells exhibited pro-apoptotic gene signatures, aged CD8 memory T cells expressed anti-apoptotic genes. Thus, the transcriptional analysis of gene expression and signaling pathways in aged T cell subsets shed light on our understanding of altered immune function with aging, which will have great potential for clinical interventions for older adults.
    Keywords:  CD4 T cells; CD8 T cells; TCRδCreERR26ZsGreen mice; aged T cells; naïve T cells
  9. EMBO Rep. 2021 Mar 03. e51606
      Reduction of mitochondrial membrane potential (Δψm ) is a hallmark of mitochondrial dysfunction. It activates adaptive responses in organisms from yeast to human to rewire metabolism, remove depolarized mitochondria, and degrade unimported precursor proteins. It remains unclear how cells maintain Δψm , which is critical for maintaining iron-sulfur cluster (ISC) synthesis, an indispensable function of mitochondria. Here, we show that yeast oxidative phosphorylation mutants deficient in complex III, IV, V, and mtDNA, respectively, exhibit activated stress responses and progressive reduction of Δψm . Extensive omics analyses of these mutants show that these mutants progressively activate adaptive responses, including transcriptional downregulation of ATP synthase inhibitor Inh1 and OXPHOS subunits, Puf3-mediated upregulation of import receptor Mia40 and global mitochondrial biogenesis, Snf1/AMPK-mediated upregulation of glycolysis and repression of ribosome biogenesis, and transcriptional upregulation of cytoplasmic chaperones. These adaptations disinhibit mitochondrial ATP hydrolysis, remodel mitochondrial proteome, and optimize ATP supply to mitochondria to convergently maintain Δψm , ISC biosynthesis, and cell proliferation.
    Keywords:  mitochondrial membrane potential; mitochondrial stress responses; oxidative phosphorylation
  10. Nat Immunol. 2021 Mar 01.
      T cells dynamically interact with multiple, distinct cellular subsets to determine effector and memory differentiation. Here, we developed a platform to quantify cell location in three dimensions to determine the spatial requirements that direct T cell fate. After viral infection, we demonstrated that CD8+ effector T cell differentiation is associated with positioning at the lymph node periphery. This was instructed by CXCR3 signaling since, in its absence, T cells are confined to the lymph node center and alternatively differentiate into stem-like memory cell precursors. By mapping the cellular sources of CXCR3 ligands, we demonstrated that CXCL9 and CXCL10 are expressed by spatially distinct dendritic and stromal cell subsets. Unlike effector cells, retention of stem-like memory precursors in the paracortex is associated with CCR7 expression. Finally, we demonstrated that T cell location can be tuned, through deficiency in CXCL10 or type I interferon signaling, to promote effector or stem-like memory fates.
  11. Dev Cell. 2021 Feb 24. pii: S1534-5807(21)00120-9. [Epub ahead of print]
      Mitochondria are essential organelles that execute and coordinate various metabolic processes in the cell. Mitochondrial dysfunction severely affects cell fitness and contributes to disease. Proper organellar function depends on the biogenesis and maintenance of mitochondria and its >1,000 proteins. As a result, the cell has evolved mechanisms to coordinate protein and organellar quality control, such as the turnover of proteins via mitochondria-associated degradation, the ubiquitin-proteasome system, and mitoproteases, as well as the elimination of mitochondria through mitophagy. Specific quality control mechanisms are engaged depending upon the nature and severity of mitochondrial dysfunction, which can also feed back to elicit transcriptional or proteomic remodeling by the cell. Here, we will discuss the current understanding of how these different quality control mechanisms are integrated and overlap to maintain protein and organellar quality and how they may be relevant for cellular and organismal health.
    Keywords:  ISR; MDVs; UPRmt; UPS; mitochondria; mitochondrial dynamics; mitophagy; mitoproteases
  12. Nutrients. 2021 Feb 28. pii: 796. [Epub ahead of print]13(3):
      Obesity is associated with an impaired balance of CD4+ T cell subsets. Both vitamin D and obesity have been reported to affect the mTOR pathway. In this study, we investigated the effects of vitamin D on CD4+ T cell subsets and the mTOR pathway. Ten-week-old male C57BL/6 mice were divided into four groups and fed diets with different fat (control or high-fat diets: CON or HFD) and vitamin D contents (vitamin D control or supplemented diets: vDC or vDS) for 12 weeks. T cells purified by negative selection were stimulated with anti-CD3/anti-CD28 mAbs and cultured for 48 h. The percentage of CD4+IL-17+ T cells was higher in the vDS than vDC groups. The CD4+CD25+Foxp3+ T cells percentage was higher in HFD than CON groups. The phospho-p70S6K/total-p70S6K ratio was lower in vDS than vDC, but the phospho-AKT/total-AKT ratio was higher in vDS than vDC groups. Hif1α mRNA levels were lower in vDS than vDC groups. These findings suggest HIF1α plays an important role in vitamin-D-mediated regulation of glucose metabolism in T cells, and dietary vitamin D supplementation may contribute to the maintenance of immune homeostasis by regulating the mTOR pathway in T cells.
    Keywords:  CD4+ T cell; HIF1α; mTOR pathway; obesity; vitamin D supplementation
  13. Nat Commun. 2021 Mar 05. 12(1): 1455
      T-cell exhaustion denotes a hypofunctional state of T lymphocytes commonly found in cancer, but how tumor cells drive T-cell exhaustion remains elusive. Here, we find T-cell exhaustion linked to overall survival in 675 hepatocellular carcinoma (HCC) patients with diverse ethnicities and etiologies. Integrative omics analyses uncover oncogenic reprograming of HCC methionine recycling with elevated 5-methylthioadenosine (MTA) and S-adenosylmethionine (SAM) to be tightly linked to T-cell exhaustion. SAM and MTA induce T-cell dysfunction in vitro. Moreover, CRISPR-Cas9-mediated deletion of MAT2A, a key SAM producing enzyme, results in an inhibition of T-cell dysfunction and HCC growth in mice. Thus, reprogramming of tumor methionine metabolism may be a viable therapeutic strategy to improve HCC immunity.