Memory CD8
+ T cells are critical for long-term immunity, but the genetic pathways governing their formation remain poorly defined. This study shows that the IL-10-IL-21-STAT3 pathway is critical for ...memory CD8
+ T cell development after acute LCMV infection. In the absence of either interleukin-10 (IL-10) and IL-21 or STAT3, virus-specific CD8
+ T cells retain terminal effector (TE) differentiation states and fail to mature into protective memory T cells that contain self-renewing central memory T cells. Expression of Eomes, BCL-6, Blimp-1, and SOCS3 was considerably reduced in STAT3-deficient memory CD8
+ T cells, and BCL-6- or SOCS3-deficient CD8
+ T cells also had perturbed memory cell development. Reduced SOCS3 expression rendered STAT3-deficient CD8
+ T cells hyperresponsive to IL-12, suggesting that the STAT3-SOCS3 pathway helps to insulate memory precursor cells from inflammatory cytokines that drive TE differentiation. Thus, memory CD8
+ T cell precursor maturation is an active process dependent on IL-10-IL-21-STAT3 signaling.
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► STAT3 promotes formation of mature, self-renewing, protective memory CD8 T cells ► IL-10+IL-21, via STAT3, enhance persistence of memory precursor cells (MPCs) ► STAT3 sustains expression of BCL-6, Eomes, and SOCS3 in memory CD8 T cells ► SOCS3 tempers STAT4 signaling in CD8 T cells and aides in MPC persistence
Tissue-resident memory T (Trm) cells provide enhanced protection against infection at mucosal sites. Here we found that CD4+ T cells are important for the formation of functional lung-resident CD8+ ...T cells after influenza virus infection. In the absence of CD4+ T cells, CD8+ T cells displayed reduced expression of CD103 (Itgae), were mislocalized away from airway epithelia, and demonstrated an impaired ability to recruit CD8+ T cells to the lung airways upon heterosubtypic challenge. CD4+ T cell-derived interferon-γ was necessary for generating lung-resident CD103+ CD8+ Trm cells. Furthermore, expression of the transcription factor T-bet was increased in “unhelped” lung Trm cells, and a reduction in T-bet rescued CD103 expression in the absence of CD4+ T cell help. Thus, CD4+ T cell-dependent signals are important to limit expression of T-bet and allow for the development of CD103+ CD8+ Trm cells in the lung airways following respiratory infection.
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•CD4+ T cells help the development of flu-specific CD103+ CD8+ Trm cells•CD4+ T cell-derived IFN-γ is necessary for generating lung CD8+ Trm cells•T-bet represses lung CD8+ Trm cell formation and induction of CD103 by TGF-β•Reduction of T-bet restores CD103 expression on “unhelped” CD8+ T cells
Tissue-resident memory T (Trm) cells protect against infection at mucosal sites. Craft and colleagues show that during viral infection, CD4+ T cell-dependent signals limit T-bet expression and allow CD103 upregulation necessary for Trm cell formation in the lung.
Regulation of metabolic pathways in the immune system provides a mechanism to actively control cellular function, growth, proliferation, and survival. Here, we report that miR-181 is a nonredundant ...determinant of cellular metabolism and is essential for supporting the biosynthetic demands of early NKT cell development. As a result, miR-181-deficient mice showed a complete absence of mature NKT cells in the thymus and periphery. Mechanistically, miR-181 modulated expression of the phosphatase PTEN to control PI3K signaling, which was a primary stimulus for anabolic metabolism in immune cells. Thus miR-181-deficient mice also showed severe defects in lymphoid development and T cell homeostasis associated with impaired PI3K signaling. These results uncover miR-181 as essential for NKT cell development and establish this family of miRNAs as central regulators of PI3K signaling and global metabolic fitness during development and homeostasis.
•miR-181 regulates cellular metabolic fitness required for robust proliferation•miR-181 is essential for NKT cell development•miR-181 is a PTEN rheostat and a central regulator of the PI3K pathway in vivo•miR-181 is a critical regulator of lymphocyte development and homeostasis
Protein kinase B (also known as AKT) and the mechanistic target of rapamycin (mTOR) are central regulators of T cell differentiation, proliferation, metabolism, and survival. Here, we show that ...during chronic murine lymphocytic choriomeningitis virus infection, activation of AKT and mTOR are impaired in antiviral cytotoxic T lymphocytes (CTLs), resulting in enhanced activity of the transcription factor FoxO1. Blockade of inhibitory receptor programmed cell death protein 1 (PD-1) in vivo increased mTOR activity in virus-specific CTLs, and its therapeutic effects were abrogated by the mTOR inhibitor rapamycin. FoxO1 functioned as a transcriptional activator of PD-1 that promoted the differentiation of terminally exhausted CTLs. Importantly, FoxO1-null CTLs failed to persist and control chronic viral infection. Collectively, this study shows that CTLs adapt to persistent infection through a positive feedback pathway (PD-1→FoxO1→PD-1) that functions to both desensitize virus-specific CTLs to antigen and support their survival during chronic viral infection.
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•TCR activation of AKT and mTOR is impaired in exhausted CTLs•Therapeutic blockade of PD-1 signaling is mTOR dependent•FoxO1 is necessary to sustain CTL responses and control chronic viral infection•FoxO1 regulates the expression and differentiation of PD-1hi exhausted CTLs
Chronic infection can lead to a state of CD8+ T cell dysfunction referred to as exhaustion. Kaech and colleagues show that the transcription factor FoxO1 promotes the differentiation and maintenance of exhausted CD8+ T cells to control chronic viral infection.
Follicular helper T (Tfh) cells are required for the establishment of T-dependent B cell memory and high affinity antibody-secreting cells. We have revealed herein opposing roles for signal ...transducer and activator of transcription 3 (STAT3) and type I interferon (IFN) signaling in the differentiation of Tfh cells following viral infection. STAT3-deficient CD4+ T cells had a profound defect in Tfh cell differentiation, accompanied by decreased germinal center (GC) B cells and antigen-specific antibody production during acute infection with lymphocytic choriomeningitis virus. STAT3-deficient Tfh cells had strikingly increased expression of a number of IFN-inducible genes, in addition to enhanced T-bet synthesis, thus adopting a T helper 1 (Th1) cell-like effector phenotype. Conversely, IFN-αβ receptor blockade restored Tfh and GC B cell phenotypes in mice containing STAT3-deficient CD4+ T cells. These data suggest mutually repressive roles for STAT3 and type I IFN signaling pathways in the differentiation of Tfh cells following viral infection.
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•STAT3 is required for Tfh and GC B cell differentiation•STAT3-deficient Tfh cells have a transcriptome similar to Th1 cells•Blockade of type I IFNs rescues STAT3-deficient Tfh cell development and function•Type I IFNs promote STAT5 binding over that of STAT3 at the Bcl6 locus
Impaired insulin-mediated suppression of hepatic glucose production (HGP) plays a major role in the pathogenesis of type 2 diabetes (T2D), yet the molecular mechanism by which this occurs remains ...unknown. Using a novel in vivo metabolomics approach, we show that the major mechanism by which insulin suppresses HGP is through reductions in hepatic acetyl CoA by suppression of lipolysis in white adipose tissue (WAT) leading to reductions in pyruvate carboxylase flux. This mechanism was confirmed in mice and rats with genetic ablation of insulin signaling and mice lacking adipose triglyceride lipase. Insulin’s ability to suppress hepatic acetyl CoA, PC activity, and lipolysis was lost in high-fat-fed rats, a phenomenon reversible by IL-6 neutralization and inducible by IL-6 infusion. Taken together, these data identify WAT-derived hepatic acetyl CoA as the main regulator of HGP by insulin and link it to inflammation-induced hepatic insulin resistance associated with obesity and T2D.
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•Insulin inhibits gluconeogenesis by suppressing lipolysis and hepatic acetyl CoA•Hyperglycemia associated with HFD is due to increased WAT-derived hepatic acetyl CoA•ATGL KOs are protected from HFD-induced insulin resistance due to decreased lipolysis•mφJNK KOs are protected from HFD-induced insulin resistance due to decreased lipolysis
Metabolic abnormalities associated with a high-fat diet are found to be driven by increased hepatic acetyl CoA levels, which are shown to be a consequence of white adipose tissue inflammation and inappropriately increased lipolysis.
Activated T cells engage aerobic glycolysis and anabolic metabolism for growth, proliferation, and effector functions. We propose that a glucose-poor tumor microenvironment limits aerobic glycolysis ...in tumor-infiltrating T cells, which suppresses tumoricidal effector functions. We discovered a new role for the glycolytic metabolite phosphoenolpyruvate (PEP) in sustaining T cell receptor-mediated Ca2+-NFAT signaling and effector functions by repressing sarco/ER Ca2+-ATPase (SERCA) activity. Tumor-specific CD4 and CD8 T cells could be metabolically reprogrammed by increasing PEP production through overexpression of phosphoenolpyruvate carboxykinase 1 (PCK1), which bolstered effector functions. Moreover, PCK1-overexpressing T cells restricted tumor growth and prolonged the survival of melanoma-bearing mice. This study uncovers new metabolic checkpoints for T cell activity and demonstrates that metabolic reprogramming of tumor-reactive T cells can enhance anti-tumor T cell responses, illuminating new forms of immunotherapy.
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•Glucose deprivation suppresses anti-tumor T cell effector functions•Glycolytic metabolite PEP sustains Ca2+ and NFAT signaling by blocking SERCA•Ca2+ signaling is an integrator of glycolytic activity and TCR signaling•T cell metabolic reprogramming enhances anti-tumor effector functions
High rates of tumor cell glycolysis suppress intratumoral T cell function by depriving T cells of glucose and the downstream metabolite phosphoenolpyruvate (PEP), which is necessary for maximal Ca2+ -NFAT signaling in T cells. Metabolic rewiring of T cells to generate PEP in glucose-poor conditions improves their anti-tumor responses.
Memory T cells are critical for long-term immunity against reinfection and require interleukin-7 (IL-7), but the mechanisms by which IL-7 controls memory T cell survival, particularly metabolic ...fitness, remain elusive. We discover that IL-7 induces expression of the glycerol channel aquaporin 9 (AQP9) in virus-specific memory CD8+ T cells, but not naive cells, and that AQP9 is vitally required for their long-term survival. AQP9 deficiency impairs glycerol import into memory CD8+ T cells for fatty acid esterification and triglyceride (TAG) synthesis and storage. These defects can be rescued by ectopic expression of TAG synthases, which restores lipid stores and memory T cell survival. Finally, we find that TAG synthesis is a central component of IL-7-mediated survival of human and mouse memory CD8+T cells. This study uncovers the metabolic mechanisms by which IL-7 tailors the metabolism of memory T cells to promote their longevity and fast response to rechallenge.
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•IL-7 induces glycerol channel AQP9 expression in CD8+ T cells•AQP9 is required for memory CD8+ T cell survival and self-renewal•AQP9 imports glycerol, promotes TAG synthesis, and sustains ATP levels in T cells•IL-7 enhances TAG synthesis to promote memory CD8+ T cell survival
Interleukin-7 induces expression of the glycerol channel aquaporin 9, allowing memory CD8+ T cells to import glycerol, use it for triglyceride synthesis and storage, and sustain ATP levels required for long-term metabolic fitness and fast responses to reinfection.
Immunotherapy has revolutionized cancer treatment, yet most patients do not respond. Here, we investigated mechanisms of response by profiling the proteome of clinical samples from advanced stage ...melanoma patients undergoing either tumor infiltrating lymphocyte (TIL)-based or anti- programmed death 1 (PD1) immunotherapy. Using high-resolution mass spectrometry, we quantified over 10,300 proteins in total and ∼4,500 proteins across most samples in each dataset. Statistical analyses revealed higher oxidative phosphorylation and lipid metabolism in responders than in non-responders in both treatments. To elucidate the effects of the metabolic state on the immune response, we examined melanoma cells upon metabolic perturbations or CRISPR-Cas9 knockouts. These experiments indicated lipid metabolism as a regulatory mechanism that increases melanoma immunogenicity by elevating antigen presentation, thereby increasing sensitivity to T cell mediated killing both in vitro and in vivo. Altogether, our proteomic analyses revealed association between the melanoma metabolic state and the response to immunotherapy, which can be the basis for future improvement of therapeutic response.
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•Proteomics of 116 melanoma tumors shows the landscapes of response to immunotherapy•Immunotherapy response was associated with enriched mitochondrial lipid metabolism•High mitochondrial metabolism led to higher antigen presentation and IFN signaling•Knockout of beta-oxidation genes reduced melanoma sensitivity to T cell killing
Proteomic profiling of melanomas from patients undergoing immunotherapy reveals key mediators of tumor immunogenicity.
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