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.
Display omitted
•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.
Display omitted
•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
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.
Display omitted
Display omitted
•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.
The differentiation of CD4+ helper T cell subsets with diverse effector functions is accompanied by changes in metabolism required to meet their bioenergetic demands. We find that follicular B helper ...T (Tfh) cells exhibited less proliferation, glycolysis, and mitochondrial respiration, accompanied by reduced mTOR kinase activity compared to T helper 1 (Th1) cells in response to acute viral infection. IL-2-mediated activation of the Akt kinase and mTORc1 signaling was both necessary and sufficient to shift differentiation away from Tfh cells, instead promoting that of Th1 cells. These findings were not the result of generalized signaling attenuation in Tfh cells, because they retained the ability to flux calcium and activate NFAT-transcription-factor-dependent cytokine production. These data identify the interleukin-2 (IL-2)-mTORc1 axis as a critical orchestrator of the reciprocal balance between Tfh and Th1 cell fates and their respective metabolic activities after acute viral infection.
Display omitted
•Tfh cells are less proliferative and metabolically active than Th1 cells•NFAT signaling is conserved in Tfh cells•Tfh cells have minimal mTOR activity and are intact in the absence of mTORc1•IL-2 suppresses Tfh cell differentiation through Akt activation
Differentiation of CD4+ helper T cells is accompanied by changes in metabolism required to meet their bioenergetic demands. Craft and colleagues demonstrate that the interleukin-2 (IL-2)-mTOR axis is a critical orchestrator of the reciprocal balance between follicular B helper T cell and T helper 1 cell fates.
More than 10% of the world's population is chronically infected with HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV), all of which can cause severe disease and death. These viruses persist in ...part because continuous antigenic stimulation causes the deterioration of virus-specific cytotoxic T lymphocyte (CTL) function and survival. Additionally, antiviral CTLs autonomously suppress their responses to limit immunopathology by upregulating inhibitory receptors such as programmed cell death 1 (PD-1). Identification and blockade of the pathways that induce CTL dysfunction may facilitate the clearance of chronic viral infections. We found that the prostaglandin E2 (PGE₂) receptors EP2 and EP4 were upregulated on virus-specific CTLs during chronic lymphocytic choriomeningitis virus (LCMV) infection and suppressed CTL survival and function. We show that the combined blockade of PGE₂ and PD-1 signaling was therapeutic in terms of improving viral control and augmenting the numbers of functional virus-specific CTLs. Thus, PGE₂ inhibition is both an independent candidate therapeutic target and a promising adjunct therapy to PD-1 blockade for the treatment of HIV and other chronic viral infections.
Summary
Immunity to many intracellular pathogens requires the proliferation, differentiation, and function of CD8+ cytotoxic T lymphocytes (CTLs). While the majority of effector CTLs die upon ...clearance of the pathogen, a small proportion of them survive to become long‐lived memory CTLs. Memory CTLs can provide protective immunity against re‐exposure to the same pathogen and are the principle motivation behind T‐cell‐ based vaccine design. While a large body of cellular immunologic research has proven invaluable to define effector and memory CTLs by their different phenotypes and functions, an emerging focus in the field has been to understand how environmental cues regulate CTL differentiation on a genomic level. Genome‐wide studies to profile transcriptional and epigenetic changes during infection have revealed that dynamic changes in DNA methylation patterns and histone modifications accompany transcriptional signatures that define and regulate CTL differentiation states. In this review, we emphasize the importance of epigenetic regulation of CD8+ T‐cell differentiation and the likely role that transcription factors play in this process.
Prolonged exposure of CD8
T cells to antigenic stimulation, as in chronic viral infections, leads to a state of diminished function termed exhaustion. We now demonstrate that even during exhaustion ...there is a subset of functional CD8
T cells defined by surface expression of SIRPα, a protein not previously reported on lymphocytes. On SIRPα
CD8
T cells, expression of co-inhibitory receptors is counterbalanced by expression of co-stimulatory receptors and it is only SIRPα
cells that actively proliferate, transcribe IFNγ and show cytolytic activity. Furthermore, target cells that express the ligand for SIRPα, CD47, are more susceptible to CD8
T cell-killing in vivo. SIRPα
CD8
T cells are evident in mice infected with Friend retrovirus, LCMV Clone 13, and in patients with chronic HCV infections. Furthermore, therapeutic blockade of PD-L1 to reinvigorate CD8
T cells during chronic infection expands the cytotoxic subset of SIRPα
CD8
T cells.
Crohn's disease (CD) is a subtype of inflammatory bowel disease (IBD) characterized by transmural disease. The concept of transmural healing (TH) has been proposed as an indicator of deep clinical ...remission of CD and as a predictor of favorable treatment endpoints. Understanding the pathophysiology involved in transmural disease is critical to achieving these endpoints. However, most studies have focused on the intestinal mucosa, overlooking the contribution of the intestinal wall in Crohn's disease. Multi-omics approaches have provided new avenues for exploring the pathogenesis of Crohn's disease and identifying potential biomarkers. We aimed to use transcriptomic and proteomic technologies to compare immune and mesenchymal cell profiles and pathways in the mucosal and submucosa/wall compartments to better understand chronic refractory disease elements to achieve transmural healing. The results revealed similarities and differences in gene and protein expression profiles, metabolic mechanisms, and immune and non-immune pathways between these two compartments. Additionally, the identification of protein isoforms highlights the complex molecular mechanisms underlying this disease, such as decreased RTN4 isoforms (RTN4B2 and RTN4C) in the submucosa/wall, which may be related to the dysregulation of enteric neural processes. These findings have the potential to inform the development of novel therapeutic strategies to achieve TH.
T follicular helper cells (Tfh) are crucial for the initiation and maintenance of germinal center (GC) reactions and high affinity, isotype-switched antibody responses. In this study, we demonstrate ...that direct TGF-β signaling to CD4 T cells is important for the formation of influenza-specific Tfh cells, GC reactions, and development of isotype-switched, flu-specific antibody responses. Early during infection, TGF-β signaling suppressed the expression of the high affinity IL-2 receptor α chain (CD25) on virus-specific CD4 T cells, which tempered IL-2 signaling and STAT5 and mammalian target of rapamycin (mTOR) activation in Tfh precursor CD4 T cells. Inhibition of mTOR allowed for the differentiation of Tfh cells in the absence of TGF-βR signaling, suggesting that TGF-β insulates Tfh progenitor cells from IL-2-delivered mTOR signals, thereby promoting Tfh differentiation during acute viral infection. These findings identify a new pathway critical for the generation of Tfh cells and humoral responses during respiratory viral infections.
During the course of many chronic viral infections, the antiviral T cell response becomes attenuated through a process that is regulated in part by the host. While elevated expression of the ...immunosuppressive cytokine IL-10 is involved in the suppression of viral-specific T cell responses, the relevant cellular sources of IL-10, as well as the pathways responsible for IL-10 induction, remain unclear. In this study, we traced IL-10 production over the course of chronic lymphocytic choriomeningitis virus (LCMV) infection in an IL-10 reporter mouse line. Using this model, we demonstrated that virus-specific T cells with reduced inflammatory function, particularly Th1 cells, display elevated and sustained IL-10 expression during chronic LCMV infection. Furthermore, ablation of IL-10 from the T cell compartment partially restored T cell function and reduced viral loads in LCMV-infected animals. We found that viral persistence is needed for sustained IL-10 production by Th1 cells and that the transcription factor BLIMP-1 is required for IL-10 expression by Th1 cells. Restimulation of Th1 cells from LCMV-infected mice promoted BLIMP-1 and subsequent IL-10 expression, suggesting that constant antigen exposure likely induces the BLIMP-1/IL-10 pathway during chronic viral infection. Together, these data indicate that effector T cells self-limit their responsiveness during persistent viral infection via an IL-10-dependent negative feedback loop.
PDF
