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. 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. Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but we also described a new syndrome we termed BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. We found that affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More broadly, we observed that genes that cause monogenic haploinsufficient diseases are generally enriched for transcription factor genes with SE architecture. We proposed that our findings had implications for superenhancer architecture and Mendelian diseases; that is, heterozygous mutations in genes that exhibit superenhancer structure may have greater significance than previously assumed. 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 this years work, we identified an unexpected role for STAT5 signaling in the death of effector memory T cells in mice and humans. We identified a patient with a heterozygous missense mutation in the coiled-coil domain of STAT5B that presented with autoimmune lymphoproliferative syndrome-like features. Similar to Stat5 - deficient mice, this patient exhibited increased CD4+ memory cells in the peripheral blood. The mutant STAT5B protein dominantly interfered with STAT5-driven transcriptional activity, leading to global downregulation of STAT5-regulated genes. Notably, CD4+ memory cells from the patient were strikingly resistant to cell death by in vitro TCR re-stimulation, a finding that was recapitulated in Stat5b deficient mice. Thus, our work indicates that in addition to other functions in T cells, including growth promoting and anti-apoptotic functions of STAT5, paradoxically, STAT5 is also a relevant factor that promotes cell death in memory T cells in mice and humans.
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| Schwartz, Daniella M; Kanno, Yuka; Villarino, Alejandro et al. (2017) JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 17:78 |
| Villarino, Alejandro V; Kanno, Yuka; O'Shea, John J (2017) Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat Immunol 18:374-384 |
| Afzali, Behdad; Grönholm, Juha; Vandrovcova, Jana et al. (2017) BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency. Nat Immunol 18:813-823 |
| O'Shea, John J; Schwartz, Daniella M; Villarino, Alejandro V et al. (2015) The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med 66:311-28 |
| Villarino, Alejandro V; Kanno, Yuka; Ferdinand, John R et al. (2015) Mechanisms of Jak/STAT signaling in immunity and disease. J Immunol 194:21-7 |
| Hirahara, Kiyoshi; Onodera, Atsushi; Villarino, Alejandro V et al. (2015) Asymmetric Action of STAT Transcription Factors Drives Transcriptional Outputs and Cytokine Specificity. Immunity 42:877-89 |
| Steward-Tharp, Scott M; Laurence, Arian; Kanno, Yuka et al. (2014) A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3. Blood 123:2978-87 |
| O'Shea, John J; Holland, Steven M; Staudt, Louis M (2013) JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 368:161-70 |
| Kontzias, Apostolos; Kotlyar, Alexander; Laurence, Arian et al. (2012) Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease. Curr Opin Pharmacol 12:464-70 |
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