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, systemic lupus erythematosus, inflammatory bowel disease and psoriasis. Conversely, mutations that affect cytokines and cytokine signal pathways underlie a variety of primary immunodeficiencies. 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 mutation of Jak3 results in a primary immunodeficiency disorder termed severe combined immunodeficiency (SCID). We have a clinical protocol that allows us to evaluate patients with suspected Jak3 deficiency. No new patients were enrolled this year. 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. These factors are called STATs (signal transducers and activators of transcription). The function of STAT proteins in immune cells has been a focus of this lab for two decades. Recent work by NIH scientists has revealed that another primary immunodeficiency syndrome, Job's or Hyperimmunoglobulin E syndrome, is due to STAT3 mutations. Based on our mouse studies, we investigated whether mutations of STAT3 in humans are associated with impaired Th17 differentiation. We found this to be the case in patients with Job's syndrome. Mutations of STAT3 underlie hyper-IgE syndrome (HIES), but deciphering STAT3s role in pathogenesis has been hampered by the lethality associated with germline deletion of Stat3. Furthermore, the mechanisms responsible for IgE hyperproduction are unknown. To better understand this complicated primary immunodeficiency, we generated a mouse model of the disease. We found that transgenic mice expressing a HIES-Stat3 allele recapitulate aspects of HIES, including elevated serum IgE. Mutant B cells display increased Ig germline transcription and switch recombination upon ex-vivo activation, demonstrating that the hyper-IgE defect is B cell intrinsic. At present, we are dissecting the relative roles of STAT3 in hematopoietic versus stromal cells. Using these mice, we are performing bone marrow transplantation experiments. These results may have important implications for patients with HIES. We have also employed new technology to begin to define STAT3 targets genome-wide. Specifically, we have used chromatin immunoprecipitation and massive parallel sequencing to comprehensively enumerate STAT3 target genes in Th17 cells. We found that STAT3 bound to multiple genes involved in Th17 cell differentiation, cell activation, proliferation, and survival, regulating both expression and epigenetic modifications. Thus, STAT3 orchestrates multiple critical aspects of T cell function in inflammation and homeostasis.

Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$166,820
Indirect Cost
Name
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Department
Type
DUNS #
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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
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
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
Laurence, Arian; Amarnath, Shoba; Mariotti, Jacopo et al. (2012) STAT3 transcription factor promotes instability of nTreg cells and limits generation of iTreg cells during acute murine graft-versus-host disease. Immunity 37:209-22
Kanno, Yuka; Vahedi, Golnaz; Hirahara, Kiyoshi et al. (2012) Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. Annu Rev Immunol 30:707-31
O'Shea, John J; Lahesmaa, Riitta; Vahedi, Golnaz et al. (2011) Genomic views of STAT function in CD4+ T helper cell differentiation. Nat Rev Immunol 11:239-50
Yang, Xiang-Ping; Ghoreschi, Kamran; Steward-Tharp, Scott M et al. (2011) Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat Immunol 12:247-54

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