bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022‒02‒13
eleven papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. J Clin Invest. 2022 Feb 10. pii: e155224. [Epub ahead of print]
      The functional integrity of CD8+ T cells is tightly coupled to metabolic reprogramming, but how oxidative stress directs CD8+ T cell metabolic fitness in the tumor microenvironment (TME) remains elusive. Here, we report that SUMO-specific protease 7 (SENP7) senses oxidative stress to maintain the CD8+ T cell metabolic state and antitumor functions. SENP7-deficient CD8+ T cells exhibited decreased glycolysis and oxidative phosphorylation, resulting in attenuated proliferation in vitro and dampened antitumor functions in vivo. Mechanistically, CD8+ T cell-derived reactive oxygen species (ROS) triggered cytosolic SENP7-mediated PTEN deSUMOylation, thereby promoting PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, lowering T cell-intrinsic ROS restricted SENP7 cytosolic translocation and repressed CD8+ T cell metabolic and functional activity in human colorectal cancer samples. Our findings reveal that SENP7, as an oxidative stress sensor, sustains CD8+ T cell metabolic fitness and effector functions and unveil an oxidative stress-sensing machinery in tumor-infiltrating CD8+ T cells.
    Keywords:  Adaptive immunity; Cancer immunotherapy; Immunology; Metabolism; T cells
  2. Immunology. 2022 Feb 10.
      Stress hormones are believed to skew the CD4 T-cell differentiation toward a Th2 response via a T cell-extrinsic mechanism. Using primary human naïve and memory CD4 T cells, here we show that both adrenergic- and glucocorticoid-mediated stress signaling pathways play a CD4 naïve T cell-intrinsic role in regulating the Th1/Th2 differentiation balance. Both stress hormones reduced theTh1 program and cytokine production by inhibiting mTORC1 signaling via two parallel mechanisms. Stress hormone signaling inhibited mTORC1 in naïve CD4 T cells 1) by affecting the PI3K/1/AKT pathway and 2) via regulating the expression of the circadian rhythm gene, period circadian regulator 1 (PER1). Both stress hormones induced the expression of PER1, which inhibited mTORC1 signaling, thus reducing Th1 differentiation. This previously unrecognized cell-autonomous mechanism connects stress hormone signaling with CD4 T-cell differentiation via mTORC1 and a specific circadian clock gene, namely PER1.
    Keywords:  Adrenergic signalling; CD4 T cells; Circadian rhythm; Neuroimmunology; Stress; T cell differentiation
  3. Sci Immunol. 2022 Feb 11. 7(68): eabl6322
      Here, we show that the capacity to manufacture IL-2 identifies constituents of the expanded CD8 T cell effector pool that display stem-like features, preferentially survive, rapidly attain memory traits, resist exhaustion, and control chronic viral challenges. The cell-intrinsic synthesis of IL-2 by CD8 T cells attenuates the ability to receive IL-2-dependent STAT5 signals, thereby limiting terminal effector formation, endowing the IL-2-producing effector subset with superior protective powers. In contrast, the non-IL-2-producing effector cells respond to IL-2 signals and gain effector traits at the expense of memory formation. Despite having distinct properties during the effector phase, IL-2-producing and nonproducing CD8 T cells appear to converge transcriptionally as memory matures to form populations with equal recall abilities. Therefore, the potential to produce IL-2 during the effector, but not memory stage, is a consequential feature that dictates the protective capabilities of the response.
  4. Carcinogenesis. 2022 Feb 09. pii: bgac017. [Epub ahead of print]
      One key reason for T cell exhaustion is continuous antigen exposure. Early exhausted T cells can reverse exhaustion and differentiate into fully functional memory T cells if removed from persisting antigen stimulation. Therefore, this study viewed T cell exhaustion as an over-activation status induced by chronic antigen stimuli. This study hypothesized that blocking TCR signal intermittently to terminate over-activation signal can defer the developmental process of T cell exhaustion. In this study, melanoma-bearing mice were treated with tacrolimus (FK506) every five days. The tumor size and tumor-infiltrating lymphocytes (TILs) were analyzed. We found that intermittent administration of tacrolimus significantly inhibited tumor growth, and this effect was mediated by CD8+T cells. Intermittent tacrolimus treatment facilitated the infiltration of CD8+TILs. RNA-seq and quantitative RT-PCR of sorted CD8+TILs showed the expression of Nr4a1 (an exhaustion-related transcription factor) and Ctla4 (a T cell inhibitory receptor) was remarkably downregulated. These results indicated that intermittently blocking TCR signal by tacrolimus can promote anti-tumor immunity and inhibit the tumor growth in melanoma-bearing mice, inhibiting the transcription of several exhaustion-related genes, such as Nr4a1 and Ctla4.
  5. Mol Cancer Res. 2022 Feb 08. pii: molcanres.0711.2021. [Epub ahead of print]
      Chimeric antigen receptor (CAR) T-cell therapies have proven to be effective in treating hematologic malignancies but demonstrate only marginal efficacy in eradicating solid tumors. Although several mechanisms can account for these differences, a major cause is thought to derive from CAR T-cell exhaustion, where chronic exposure to tumor antigen can activate feedback pathways that suppress CAR T-cell cytotoxicity. We describe here a strategy to reverse this CAR T-cell exhaustion using a universal anti-fluorescein CAR that concurrently serves as 1) a cancer recognition receptor that enables engagement of multiple cancer cell clones upon addition of a cocktail of bispecific fluorescein-linked tumor-targeting ligands, and 2) a drug-internalizing receptor that mediates uptake of a CAR T-cell activator comprised of fluorescein linked to an immune stimulant. By attaching a Toll-like receptor 7 agonist (TLR7-1A) to fluorescein, we enable the anti-fluorescein CAR to bind and internalize TLR7-1A, leading to both downregulation of exhaustion markers (i.e. PD-1, TIM3, LAG3) and reactivation of exhausted CAR T-cells without causing the toxicities commonly associated with systemic administration of TLR7 agonists. The resulting rejuvenated CAR T-cells are observed to regress otherwise refractory solid tumors. Moreover, because no other immune cells are altered by this treatment, the data demonstrate that the exhaustion state of the CAR T-cells constitutes a major property that determines the efficacies of CAR T-cell therapies in solid tumors. Implications: A novel strategy for rejuvenating exhausted CAR T-cells is described that promotes downregulation of exhaustion markers and renewed eradication of cancer cells in a tumor mass.
  6. Nat Commun. 2022 Feb 10. 13(1): 805
      T follicular helper (Tfh) cells provide signals to initiate and maintain the germinal center (GC) reaction and are crucial for the generation of robust, long-lived antibody responses, but how the GC microenvironment affects Tfh cells is not well understood. Here we develop an in vivo T cell-intrinsic CRISPR-knockout screen to evaluate Tfh and Th1 cells in an acute viral infection model to identify regulators of Tfh cells in their physiological setting. Using a screen of druggable-targets, alongside genetic, transcriptomic and cellular analyses, we identify a function of HIF-1α in suppressing mTORC1-mediated and Myc-related pathways, and provide evidence that VHL-mediated degradation of HIF-1α is required for Tfh development; an expanded in vivo CRISPR screen reveals multiple components of these pathways that regulate Tfh versus Th1 cells, including signaling molecules, cell-cycle regulators, nutrient transporters, metabolic enzymes and autophagy mediators. Collectively, our data serve as a resource for studying Tfh versus Th1 decisions, and implicate the VHL-HIF-1α axis in fine-tuning Tfh generation.
  7. Cell Metab. 2022 Feb 01. pii: S1550-4131(22)00022-5. [Epub ahead of print]
      Metabolism of cancer cells is geared toward biomass production and proliferation. Since the metabolic resources within the local tissue are finite, this can lead to nutrient depletion and accumulation of metabolic waste. To maintain growth in these conditions, cancer cells employ a variety of metabolic adaptations, the nature of which is collectively determined by the physiology of their cell of origin, the identity of transforming lesions, and the tissue in which cancer cells reside. Furthermore, select metabolites not only serve as substrates for energy and biomass generation, but can also regulate gene and protein expression and influence the behavior of non-transformed cells in the tumor vicinity. As they grow and metastasize, tumors can also affect and be affected by the nutrient distribution within the body. In this hallmark update, recent advances are incorporated into a conceptual framework that may help guide further research efforts in exploring cancer cell metabolism.
  8. Nat Rev Endocrinol. 2022 Feb 10.
      Organismal ageing is accompanied by progressive loss of cellular function and systemic deterioration of multiple tissues, leading to impaired function and increased vulnerability to death. Mitochondria have become recognized not merely as being energy suppliers but also as having an essential role in the development of diseases associated with ageing, such as neurodegenerative and cardiovascular diseases. A growing body of evidence suggests that ageing and age-related diseases are tightly related to an energy supply and demand imbalance, which might be alleviated by a variety of interventions, including physical activity and calorie restriction, as well as naturally occurring molecules targeting conserved longevity pathways. Here, we review key historical advances and progress from the past few years in our understanding of the role of mitochondria in ageing and age-related metabolic diseases. We also highlight emerging scientific innovations using mitochondria-targeted therapeutic approaches.
  9. Immunity. 2022 Feb 08. pii: S1074-7613(22)00033-4. [Epub ahead of print]55(2): 210-223
      Nutrition affects all physiological processes including those linked to the development and function of our immune system. Here, we discuss recent evidence and emerging concepts supporting the idea that our newfound relationship with nutrition in industrialized countries has fundamentally altered the way in which our immune system is wired. This will be examined through the lens of studies showing that mild or transient reductions in dietary intake can enhance protective immunity while also limiting aberrant inflammatory responses. We will further discuss how trade-offs and priorities begin to emerge in the context of severe nutritional stress. In those settings, specific immunological functions are heightened to re-enforce processes and tissue sites most critical to survival. Altogether, these examples will emphasize the profound influence nutrition has over the immune system and highlight how a mechanistic exploration of this cross talk could ultimately lead to the design of novel therapeutic approaches that prevent and treat disease.
    Keywords:  caloric restriction mimetics; dietary restriction; immunology; microbiota; nutrition; undernutrition
  10. Cell Immunol. 2022 Feb 07. pii: S0008-8749(22)00009-0. [Epub ahead of print]373 104485
      The metabolite itaconate plays a critical role in modulating inflammatory responses among macrophages infected with intracellular pathogens. However, the ability of itaconate to influence developing T cells responses is poorly understood. To determine if itaconate contributes to the quality of T cell mediated immunity against intracellular infection, we used Francisella tularensis as a model of vaccine induced immunity. Following vaccination with F. tularensis live vaccine strain, itaconate deficient mice (ACOD KO) had a prolonged primary infection but were more resistant to secondary infection with virulent F. tularensis relative to wild type controls. Improved resistance to secondary challenge was associated with both increased numbers and effector function of CD4+ and CD8+ T cells in ACOD KO mice. However, additional data suggest that improved T cell responses was not T cell intrinsic. These data underscore the consequences of metabolic perturbations within antigen presenting cells on the development of vaccine-elicited immune responses.
    Keywords:  Francisella tularensis; Immunometabolism; Itaconate; Lung; Macrophage; T cell