Cytokine Signaling, Immunoregulation and Autoimmune and Immunodeficiency Diseases

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications & trials

Abstract

STAT5 encompasses two genes, STAT5a and STAT5b and using a series of STAT5-deficient mice we demonstrated that STAT5 is a master regulator of energy and amino acid metabolism in CD4+ T helper cells. We established that STAT5 regulates the activity of key metabolically relevant biochemical pathways including: AKT, mTOR and MYC. PIK3d (encoded by PIK3CD) is a key enzyme that is activated downstream by many cytokines and gain-of-function mutations of this gene underlie a primary immunodeficiency disorder. Using patient samples and mouse model, we demonstrated the mutant version of PI3Kd dysregulates metabolism and promotes exaggerated STAT5 signaling. This is associated with reduced CD8 T cell memory. Patients with loss-of-function mutations of STAT1 exhibit viral and bacterial susceptibility. This year, we reported that mice lacking STAT1 in T cells control parasitic infection. However, as a consequence of infection, they exhibit lethal immunopathology associated with a type 1 (interferon gamma) response, reduced IL-10 generation and increased IL-13 production. We also showed that STAT1 contributes directly to regulation of Il10, Maf, and Irf4. Conversely, STAT1 gain-of-function (GOF) mutations underlie heterogenous disorders. Such patients exhibit both immunodeficiency and autoimmunity (including SLE, scleroderma and related disorders). To better understand immunopathogenic mechanisms of disease, we developed a STAT1 GOF mouse. We found that these mice have increased susceptibility to viral infection, including SARS-CoV2. These mice exhibit a cytokine storm-like phenotype. We found that exogenous interferon gamma can reverse aspects of the pathology. This year we identified patients with STAT6 gain-of-function variants, a new autosomal dominant primary atopic disorder. These patients have early-life onset allergic immune dysregulation, treatment-resistant atopic dermatitis, hypereosinophilia as well as eosinophilic gastrointestinal disease, asthma, increased levels of IgE, food allergies, and anaphylaxis. These STAT6 variants exhibited increased STAT6 phosphorylation and transcriptional activity. In addition, we also studied patients with disabling pansclerotic morphea and investigated four patients with an autosomal dominant pattern of disease. These patients were found to have STAT4 mutations with functional consequences consistent with a gain-of-function activity. Fibroblasts from patients produced increased levels of interleukin-6 and impaired wound healing. Treatment of these patients with JAK inhibitors led to improvement. We previously identified Furin, encoded by PCSK3, as a prominent IL-12/STAT4-dependent target that processes the cytokine transforming growth factor b (TGFb; Pesu et al, Nature, 2008; Sciume et al, Immunity, 2020). In the present work, we used conditional T cell deletion of PCSK3 in mice and examined the role of furin CD8 T cells. We found that furin deficiency results in enhanced interferon gamma production and improved viral clearance. Following on our interest in TGFb, we showed that this cytokine increases expression of phosphofructokinase-1 (encoded by PFKL) and thus promotes a glycolytic program. However, this action of TGFb correlates with increased lethality of sepsis and coagulopathy; this transcriptomic program correlated with myeloid gene expression in COVID-19.