Tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3) is an adapter protein with many context-specific functions. Early studies of lymphocyte TRAF3 hinted at TRAF3's importance for T cell ...function, but elucidation of specific mechanisms was delayed by early lethality of globally TRAF3
mice. Development of a conditional TRAF3-deficient mouse enabled important descriptive and mechanistic insights into how TRAF3 promotes optimal T cell function. Signaling through the T cell antigen receptor (TCR) fails to induce normal proliferation and survival in TRAF3
T cells, and TCR-activated cells
and
have deficient cytokine production. These defects can be traced to incorrect localization and function of negative regulatory phosphatases acting at different parts of the signaling cascade, as can dysregulated effector responses and memory T cell homeostasis
and an enlarged regulatory T cell (Treg) compartment. The important regulatory activity of TRAF3 is also evident at members of the TNFR superfamily and cytokine receptors. Here, we review significant advances in mechanistic understanding of how TRAF3 regulates T cell differentiation and function, through modulation of signaling through the TCR, costimulatory receptors, and cytokine receptors. Finally, we briefly discuss the recent identification of families carrying single allele loss-of-function mutations in
, and compare the findings in their T cells with the T cell defects identified in mice whose T cells completely lack T cell TRAF3. Together, the body of work describing TRAF3-mediated regulation of T cell effector function and differentiation frame TRAF3 as an important modulator of T cell signal integration.
CKD is associated with a complex state of immune dysfunction characterized by immune depression, predisposing patients to infections, and immune activation, resulting in inflammation that associates ...with higher risk of cardiovascular disease. Physical exercise may enhance immune function and exert anti-inflammatory effects, but such effects are unclear in CKD. We investigated the separate effects of acute and regular moderate-intensity aerobic exercise on neutrophil degranulation (elastase release), activation of T lymphocytes (CD69 expression) and monocytes (CD86 and HLA-DR expression), and plasma inflammatory markers (IL-6, IL-10, soluble TNF-receptors, and C-reactive protein) in patients with predialysis CKD. A single 30-minute (acute) bout of walking induced a normal pattern of leukocyte mobilization and had no effect on T-lymphocyte and monocyte activation but improved neutrophil responsiveness to a bacterial challenge in the postexercise period. Furthermore, acute exercise induced a systemic anti-inflammatory environment, evidenced by a marked increase in plasma IL-10 levels (peaked at 1 hour postexercise), that was most likely mediated by increased plasma IL-6 levels (peaked immediately postexercise). Six months of regular walking exercise (30 min/d for 5 times/wk) exerted anti-inflammatory effects (reduction in the ratio of plasma IL-6 to IL-10 levels) and a downregulation of T-lymphocyte and monocyte activation, but it had no effect on circulating immune cell numbers or neutrophil degranulation responses. Renal function, proteinuria, and BP were also unaffected. These findings provide compelling evidence that walking exercise is safe with regard to immune and inflammatory responses and has the potential to be an effective anti-inflammatory therapy in predialysis CKD.
Self‐assembled monolayers (SAMs) are becoming widely utilized as hole‐selective layers in high‐performance p‐i‐n architecture perovskite solar cells. Ultrasonic spray coating and airbrush coating are ...demonstrated here as effective methods to deposit MeO‐2PACz; a carbazole‐based SAM. Potential dewetting of hybrid perovskite precursor solutions from this layer is overcome using optimized solvent rinsing protocols. The use of air‐knife gas‐quenching is then explored to rapidly remove the volatile solvent from an MAPbI3 precursor film spray‐coated onto an MeO‐2PACz SAM, allowing fabrication of p‐i‐n devices with power conversion efficiencies in excess of 20%, with all other layers thermally evaporated. This combination of deposition techniques is consistent with a rapid, roll‐to‐roll manufacturing process for the fabrication of large‐area solar cells.
Carbazole‐based self‐assembled monolayers are becoming a dominant hole‐transporting layer in p‐i‐n perovskite solar cells, combining stability, efficiency, and low‐cost. Here, spray coating and airbrush pen coating of MeO‐2PACz are used to fabricate high‐quality transport layers. This is combined with gas‐quenched spray‐coated perovskite layers, to realize solar cells with power conversion efficiencies in excess of 20%.
Type I interferons (IFNs) are among the most powerful tools that host cells deploy against intracellular pathogens. Their effectiveness is due both to the rapid, directly antiviral effects of ...IFN-stimulated gene products and to the effects of type I IFN on responding immune cells. Type I IFN signaling through its receptor, IFNAR, is tightly regulated at multiple steps in the signaling cascade, including at the level of IFNAR downstream effectors, which include the kinase JAK1 and the transcriptional regulator STAT1. Here, we found that tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3) enhanced the activation of JAK1 and STAT1 specifically in CD4
T cells by preventing recruitment of the negative regulatory phosphatase PTPN22 to the IFNAR complex. The balance between signals through IFNAR and other cytokine receptors influences CD4
T cell differentiation and function during infections. Our work reveals TRAF3 and PTPN22 as key regulators of CD4
T cell activation by type I IFNs.
Succinate dehydrogenase (SDH) loss-of-function mutations drive succinate accumulation in tumor microenvironments, for example in the neuroendocrine tumors pheochromocytoma (PC) and paraganglioma ...(PG). Control of innate immune cell activity by succinate is described, but effects on T cells have not been interrogated. Here we report that exposure of human CD4+ and CD8+ T cells to tumor-associated succinate concentrations suppresses degranulation and cytokine secretion, including of the key anti-tumor cytokine interferon-γ (IFN-γ). Mechanistically, this is associated with succinate uptake—partly via the monocarboxylate transporter 1 (MCT1)—inhibition of succinyl coenzyme A synthetase activity and impaired glucose flux through the tricarboxylic acid cycle. Consistently, pharmacological and genetic interventions restoring glucose oxidation rescue T cell function. Tumor RNA-sequencing data from patients with PC and PG reveal profound suppression of IFN-γ-induced genes in SDH-deficient tumors compared with those with other mutations, supporting a role for succinate in modulating the anti-tumor immune response in vivo.
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•Succinate inhibits CD4+ and CD8+ T cell effector function, including IFN-γ secretion•T cells readily assimilate succinate from their environment•Succinate inhibits T cell succinyl-CoA synthetase activity and the TCA cycle•Neuroendocrine tumors with succinate dehydrogenase mutations have poor IFN-γ responses
Succinate dehydrogenase (SDH) mutations drive succinate accumulation in tumor microenvironments. Gudgeon et al. observe that succinate suppresses T cell degranulation and cytokine secretion, particularly IFN-γ. This is associated with succinate uptake, inhibited succinyl-CoA synthetase activity, and impaired tricarboxylic acid cycle flux. Consistently, IFN-γ-induced genes are suppressed in SDH-deficient neuroendocrine tumors.
T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of the immune system. Approximately 20% of paediatric and 50% of adult T-ALL patients have refractory disease or relapse and die from the ...disease. To improve patient outcome new therapeutics are needed. With the aim to identify new therapeutic targets, we combined the analysis of T-ALL gene expression and metabolism to identify the metabolic adaptations that T-ALL cells exhibit. We found that glutamine uptake is essential for T-ALL proliferation. Isotope tracing experiments showed that glutamine fuels aspartate synthesis through the TCA cycle and that glutamine and glutamine-derived aspartate together supply three nitrogen atoms in purines and all but one atom in pyrimidine rings. We show that the glutamate-aspartate transporter EAAT1 (SLC1A3), which is normally expressed in the central nervous system, is crucial for glutamine conversion to aspartate and nucleotides and that T-ALL cell proliferation depends on EAAT1 function. Through this work, we identify EAAT1 as a novel therapeutic target for T-ALL treatment.
Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 ...diabetes drug, is a sodium glucose co-transporter 2 (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the effects of SGLT2 inhibitors on human T cell function have not been extensively explored. Here, we show that canagliflozin-treated T cells are compromised in their ability to activate, proliferate, and initiate effector functions. Canagliflozin inhibits T cell receptor signaling, impacting on ERK and mTORC1 activity, concomitantly associated with reduced c-Myc. Compromised c-Myc levels were encapsulated by a failure to engage translational machinery resulting in impaired metabolic protein and solute carrier production among others. Importantly, canagliflozin-treated T cells derived from patients with autoimmune disorders impaired their effector function. Taken together, our work highlights a potential therapeutic avenue for repurposing canagliflozin as an intervention for T cell-mediated autoimmunity.
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•Canagliflozin (cana) inhibits human T cell effector function•Cana compromises T cell receptor signaling•Cana impairs the activity of ERK, mTORC, and Myc, preventing metabolic rewiring•Cana impairs the effector function of T cells derived from patients with autoimmunity
Jenkins et al. report that the SGLT2 inhibitor, canagliflozin, compromises human T cell effector function. Canagliflozin prevents T cell activation and proliferation by antagonizing TCR signaling, impairing the activity of c-Myc, leading to a failure to engage in metabolic rewiring. In vitro, canagliflozin impairs T cell function in patients with autoimmunity.
Increasing evidence indicates that exercise has beneficial effects on chronic inflammation, cardiorespiratory function, muscle and bone strength and metabolic markers in adults with chronic kidney ...disease (CKD), kidney failure or kidney transplants. However, the mechanisms that underlie these benefits have received little attention, and the available clinical evidence is mainly from small, short-duration (<12 weeks) exercise intervention studies. The available data, mainly from patients with CKD or on dialysis, suggest that exercise-mediated shifts towards a less inflammatory immune cell profile, enhanced activity of the NRF2 pathway and reduced monocyte infiltration into adipose tissue may underlie improvements in inflammatory biomarkers. Exercise-mediated increases in nitric oxide release and bioavailability, reduced angiotensin II accumulation in the heart, left ventricular remodelling and reductions in myocardial fibrosis may contribute to improvements in left ventricular hypertrophy. Exercise stimulates an anabolic response in skeletal muscle in CKD, but increases in mitochondrial mass and satellite cell activation seem to be impaired in this population. Exercise-mediated activation of the canonical wnt pathway may lead to bone formation and improvements in the levels of the bone-derived hormones klotho and fibroblast growth factor 23 (FGF23). Longer duration studies with larger sample sizes are needed to confirm these mechanisms in CKD, kidney failure and kidney transplant populations and provide evidence for targeted exercise interventions.
Tissue residency is considered a defining feature of the innate lymphoid cell (ILC) populations located within mucosal and adipose tissues. ILCs are also present within all lymphoid tissues, but ...whether ILCs migrate between lymphoid and nonlymphoid sites and in what context is poorly understood. To determine whether migratory ILCs exist within peripheral lymph nodes (LNs), we labeled all cells within the brachial LN (bLN) of transgenic mice expressing a photoconvertible fluorescent protein by direct exposure to light. Tracking of cellular changes in the labeled LN revealed the gradual migration of new ILCs into the tissue, balanced by egress of ILCs dependent on sphingosine-1-phosphate receptors. Most of the migratory ILCs were ILC1s, entering LNs directly from the circulation in a CD62L- and CCR7-dependent manner and thus behaving like conventional natural killer (cNK) cells. Upon egress, both ILC1s and cNK cells were found to recirculate through peripheral LNs. A distinct population of migratory ILC2s were detected in the LN, but most of the ILC3s were tissue resident. Functionally, both migratory and resident ILC1s within LNs were able to rapidly produce IFN-γ to support the generation of robust T
1 T cell responses after immunization. Thus, migratory and resident ILC populations exist within peripheral LNs, with ILC1s, akin to cNK cells, able to traffic into these tissues where they can contribute to the initiation of adaptive immunity.
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