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SUMMARYInborn Errors of Metabolism (IEM) and Immunity (IEI) are Mendelian diseases in which complex phenotypes and patient rarity can limit clinical annotations. Few genes are assigned to both IEM and IEI, but immunometabolic demands suggest functional overlap is underestimated. We applied CRISPR screens to test IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable crossover. Analysis of IEM showed N-linked glycosylation and thede novohexosamine synthesis enzyme,Gfpt1, are critical for T cell expansion and function. Interestingly,Gfpt1-deficient TH1 cells were more affected than TH17 cells, which had increasedNagkfor salvage UDP-GlcNAc synthesis. Screening IEI genes showed the transcription factorBcl11bpromotes CD4+T cell mitochondrial activity andMcl1expression necessary to prevent metabolic stress. These data illustrate a high degree of functional overlap of IEM and IEI genes and point to potential immunometabolic mechanisms for a previously unappreciated set of these disorders.HIGHLIGHTSInborn errors of immunity and metabolism have greater overlap than previously knownGfpt1deficiency causes an IEM but also selectively regulates T cell subset fateLoss ofBcl11bcauses a T cell deficiency IEI but also harms mitochondrial functionMany IEM may have immune defects and IEI may be driven by metabolic mechanisms

Heat is a cardinal feature of inflammation. Despite temperature variability and dependence of enzymes and complexes, how heat and fever affect immune cells remains uncertain. We found that heat broadly increased inflammatory activity of CD4+T cell subsets and decreased Treg suppressive function. Th1 cells, however, also selectively developed mitochondrial dysfunction with high levels of ROS production and DNA damage. This led Th1 cells to undergoTp53-dependent death, which was required to minimize the accumulation of mutations in heat and inflammation. Th1 cells with similar DNA damage signatures were also detected in Crohn’s disease and rheumatoid arthritis. Fever and inflammation-associated heat thus selectively induce mitochondrial stress and DNA damage in activated Th1 cells that requires p53 to maintain genomic integrity of the T cell repertoire.One Sentence SummaryFever temperatures augment CD4+T cell-mediated inflammation but induce differential metabolic stress and DNA damage in T cell subsets, with Th1 cells selectively sensitive and dependent on p53 to induce apoptosis and maintain genomic integrity.

Background & Aims CD4+ T cells are regulated by activating and inhibitory cues, and dysregulation of these proper regulatory inputs predisposes these cells to aberrant inflammation and exacerbation of disease. We investigated the role of the inhibitory receptor paired immunoglobulin-like receptor B (PIR-B) in the regulation of the CD4+ T-cell inflammatory response and exacerbation of the colitic phenotype. Methods We used Il10-/- spontaneous and CD4+CD45RBhi T-cell transfer models of colitis with PIR-B-deficient (Pirb-/-) mice. Flow cytometry, Western blot, and RNA sequencing analysis was performed on wild-type and Pirb-/- CD4+ T cells. In silico analyses were performed on RNA sequencing data set of ileal biopsy samples from pediatric CD and non–inflammatory bowel disease patients and sorted human memory CD4+ T cells. Results We identified PIR-B expression on memory CD4+ interleukin (IL)17a+ cells. We show that PIR-B regulates CD4+ T-helper 17 cell (Th17)-dependent chronic intestinal inflammatory responses and the development of colitis. Mechanistically, we show that the PIR-B– Src-homology region 2 domain-containing phosphatase-1/2 axis tempers mammalian target of rapamycin complex 1 signaling and mammalian target of rapamycin complex 1–dependent caspase-3/7 apoptosis, resulting in CD4+ IL17a+ cell survival. In silico analyses showed enrichment of transcriptional signatures for Th17 cells (RORC, RORA, and IL17A) and tissue resident memory (HOBIT, IL7R, and BLIMP1) networks in PIR-B+ murine CD4+ T cells and human CD4+ T cells that express the human homologue leukocyte immunoglobulin-like receptor subfamily B member 3 (LILRB3). High levels of LILRB3 expression were associated strongly with mucosal injury and a proinflammatory Th17 signature, and this signature was restricted to a treatment-naïve, severe pediatric CD population. Conclusions Our findings show an intrinsic role for PIR-B/LILRB3 in the regulation of CD4+ IL17a+ T-cell pathogenic memory responses., Graphical abstract

Cancer cells characteristically consume glucose through Warburg metabolism1, a process that forms the basis of tumour imaging by positron emission tomography (PET). Tumour-infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells2–4. However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear. Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME. Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models. By contrast, cancer cells showed the highest uptake of glutamine. This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine. Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME. Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively. Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME. Positron emission tomography measurements of nutrient uptake in cells of the tumour microenvironment reveal cell-intrinsic partitioning in which glucose uptake is higher in myeloid cells, whereas glutamine is preferentially acquired by cancer cells.

Cancer cells characteristically consume glucose through Warburg metabolism

BACKGROUND: The GTPase of immunity-associated protein 5 is essential for lymphocyte homeostasis and survival. Recently, human GIMAP5 SNPs have been linked with an increased risk for asthma, while the loss of Gimap5 in mice has been associated with severe CD4(+) T celldriven immune pathology. OBJECTIVE: To identify the molecular and cellular mechanisms by which Gimap5-deficiency predisposes to allergic airway disease. METHODS: CD4(+) T cell polarization and the development of pathogenic CD4(+) T cells were assessed in Gimap5-deficient mice and a human patient with a GIMAP5 loss-of-function (LOF) mutation. House dust mite (HDM)-induced airway inflammation was assessed using a complete Gimap5 LOF (Gimap5(sph/sph)) and conditional Gimap5(fl/fl) Cd4(Cre/ert2) mice. RESULTS: GIMAP5 LOF mutations in both mice and humans are associated with spontaneous polarization towards pathogenic T(H)17 and T(H)2 cells in vivo. Mechanistic studies in vitro reveal that impairment of Gimap5-deficient T(H) cell differentiation is associated with increased DNA damage, particularly during T(H)1 polarizing conditions. The DNA damage in Gimap5-deficient CD4(+) T cells could be controlled by TGFβ, thereby promoting T(H)17 polarization. When challenged with HDM in vivo, Gimap5-deficient mice displayed an exacerbated asthma phenotype (inflammation and airway hyperresponsiveness) with increased development of T(H)2, T(H)17, and pathogenic T(H)17/ T(H)2 cells. CONCLUSION: Activation of Gimap5-deficient CD4(+) T cells is associated with increased DNA damage and reduced survival that can be overcome by TGFβ. This leads to a selective survival of pathogenic T(H)17 cells, but also T(H)2 in humans and mice, ultimately promoting allergic airway disease.

GTPase of immunity-associated protein 5 (Gimap5) is linked with lymphocyte survival, autoimmunity, and colitis, but its mechanisms of action are unclear. Here, we show that Gimap5 is essential for the inactivation of glycogen synthase kinase-3β (GSK3β) following T cell activation. In the absence of Gimap5, constitutive GSK3β activity constrains c-Myc induction and NFATc1 nuclear import, thereby limiting productive CD4+ T cell proliferation. Additionally, Gimap5 facilitates Ser389 phosphorylation and nuclear translocation of GSK3β, thereby limiting DNA damage in CD4+ T cells. Importantly, pharmacological inhibition and genetic targeting of GSK3β can override Gimap5 deficiency in CD4+ T cells and ameliorates immunopathology in mice. Finally, we show that a human patient with a GIMAP5 loss-of-function mutation has lymphopenia and impaired T cell proliferation in vitro that can be rescued with GSK3 inhibitors. Given that the expression of Gimap5 is lymphocyte-restricted, we propose that its control of GSK3β is an important checkpoint in lymphocyte proliferation., Loss of function GIMAP5 mutation is associated with lymphopenia, but how it mediates T cell homeostasis is unclear. Here the authors study Gimap5−/− mice and a patient with GIMAP5 deficiency to show how this GTPAse negatively regulates GSK3β activity to prevent DNA damage and cell death.

Background GTPase of immunity-associated protein 5 (GIMAP5) is essential for lymphocyte homeostasis and survival. Recently, human GIMAP5 single nucleotide polymorphisms have been linked to an increased risk for asthma, whereas loss of Gimap5 in mice has been associated with severe CD4+ T cell–driven immune pathology. Objective We sought to identify the molecular and cellular mechanisms by which Gimap5 deficiency predisposes to allergic airway disease. Methods CD4+ T-cell polarization and development of pathogenic CD4+ T cells were assessed in Gimap5-deficient mice and a human patient with a GIMAP5 loss-of-function (LOF) mutation. House dust mite–induced airway inflammation was assessed by using a complete Gimap5 LOF (Gimap5sph/sph) and conditional Gimap5fl/flCd4Cre/ert2 mice. Results GIMAP5 LOF mutations in both mice and human subjects are associated with spontaneous polarization toward pathogenic TH17 and TH2 cells in vivo. Mechanistic studies in vitro reveal that impairment of Gimap5-deficient TH cell differentiation is associated with increased DNA damage, particularly during TH1-polarizing conditions. DNA damage in Gimap5-deficient CD4+ T cells could be controlled by TGF-β, thereby promoting TH17 polarization. When challenged with house dust mite in vivo, Gimap5-deficient mice displayed an exacerbated asthma phenotype (inflammation and airway hyperresponsiveness), with increased development of TH2, TH17, and pathogenic TH17/TH2 cells. Conclusion Activation of Gimap5-deficient CD4+ T cells is associated with increased DNA damage and reduced survival that can be overcome by TGF-β. This leads to selective survival of pathogenic TH17 cells but also TH2 cells in human subjects and mice, ultimately promoting allergic airway disease.