Cytokine Signaling and Primary Immunodeficiency

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Cytokines represent a large number of secreted proteins that regulate cell growth and differentiation. These factors are especially important in regulating immune and inflammatory responses, and in regulating lymphoid development and differentiation. Not surprisingly, cytokines are critical in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, lupus, inflammatory bowel disease, psoriasis, atopic dermatitis, allergies and asthma. Conversely, mutations that affect cytokines and cytokine signal pathways underlie a variety of primary immunodeficiencies, which may present with host defense defects with or without autoimmune and allergic features. We discovered human Jak3, a kinase essential for signaling by cytokines that bind the common gamma chain, gc (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21). We found that a mutation of Jak3 results in the primary immunodeficiency disorder SCID. After activation of receptor-associated Jaks, the next step in signal transduction is the activation of latent, cytosolic transcription factors that can also bind activated cytokine receptors, known as STATs. Work by us and other NIH scientists have revealed that mutations of STAT3 underlie the autosomal dominant form of hyperimmunoglobulin E syndrome (HIES). This work led us to understand the impact of STATs on transcriptomic regulation and epigenomic organization of lymphocytes. We found that STATs have a major impact on enhancers and superenhancers. We are continuing work on STAT3 and HIES with other investigators at NIH. In our previous work, we have identified BACH2 as a critical transcription for T and B cell homeostasis. We also discovered that BACH2 locus also has a very striking super-enhancer architecture. We also described a new syndrome we termed BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Our previous work has documented critical functions of STAT5 in CD4+ helper T cells, ranging from suppression of follicular helper T cell function to promotion of regulatory T cells. STAT5 is also known to favor the generation and survival of memory T cells. In a patient that presented with autoimmune lymphoproliferative syndrome-like features, we identified a heterozygous missense mutation in the coiled-coil domain of STAT5B. This mutant STAT5B protein dominantly interfered with STAT5-driven transcriptional activity, leading to global downregulation of STAT5-regulated genes. CD4+ memory cells from the patient were strikingly resistant to cell death by in vitro TCR re-stimulation. This work showed that in addition its growth promoting and anti-apoptotic functions, STAT5 is also a relevant factor that promotes cell death in memory T cells in mice and humans.