{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:35:11Z","timestamp":1779237311548,"version":"3.51.4"},"reference-count":86,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2009,1,1]],"date-time":"2009-01-01T00:00:00Z","timestamp":1230768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>\u201cExperiments of nature\u201d due to single gene mutations resulting in human immunodeficiency states have revealed critical roles for several genes in regulating lymphocyte development and the generation of protective immunity. Recently, heterozygous mutations in STAT3 were found to cause autosomal dominant hyper-IgE syndrome, a condition affecting not only the immune system but also other mesenchymal and ectodermal tissues, including bones, cranium, teeth, and skin. STAT proteins operate to integrate signals from surface receptors, including cytokine receptors, that regulate growth and differentiation of multiple cell lineages. In this article, we will review how the study of STAT3 deficiency in humans and mice has highlighted nonredundant roles of STAT3, and of specific cytokines, in diverse cellular processes such as antimicrobial immunity and protection at epithelial barriers, the generation of functional humoral immune responses, bone formation, and keratinocyte biology.<\/jats:p>","DOI":"10.4049\/jimmunol.182.1.21","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T23:17:12Z","timestamp":1397863032000},"page":"21-28","source":"Crossref","is-referenced-by-count":49,"title":["Insights into the Role of STAT3 in Human Lymphocyte Differentiation as Revealed by the Hyper-IgE Syndrome"],"prefix":"10.1093","volume":"182","author":[{"given":"Stuart G","family":"Tangye","sequence":"first","affiliation":[{"name":"Immunology and Inflammation Program, Garvan Institute of Medical Research , Darlinghurst,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew C","family":"Cook","sequence":"additional","affiliation":[{"name":"John Curtin School of Medical Research, Australian National University , Canberra,","place":["Australia"]},{"name":"Department of Immunology, The Canberra Hospital , Woden,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A","family":"Fulcher","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute of Clinical Pathology and Medical Research, Westmead Hospital , Westmead,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,1,1]]},"reference":[{"key":"2025032622105533700_R1","first-page":"900","article-title":"Regulation of JAK-STAT signalling in the immune system.","volume-title":"Nat Rev Immunol","year":"2003"},{"key":"2025032622105533700_R2","first-page":"651","article-title":"Stats: transcriptional control and biological impact.","volume-title":"Nat. Rev. Mol. Cell Biol.","year":"2002"},{"key":"2025032622105533700_R3","first-page":"2623","article-title":"The JAK-STAT signaling pathway: input and output integration.","volume-title":"J. Immunol.","year":"2007"},{"key":"2025032622105533700_R4","first-page":"477","article-title":"Cytokine signaling modules in inflammatory responses.","volume-title":"Immunity","year":"2008"},{"key":"2025032622105533700_R5","first-page":"835","article-title":"Human primary immunodeficiency diseases.","volume-title":"Immunity","year":"2007"},{"key":"2025032622105533700_R6","first-page":"65","article-title":"Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID).","volume-title":"Nature","year":"1995"},{"key":"2025032622105533700_R7","first-page":"745","article-title":"Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity.","volume-title":"Immunity","year":"2006"},{"key":"2025032622105533700_R8","first-page":"e1584","article-title":"Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation.","volume-title":"Pediatrics","year":"2006"},{"key":"2025032622105533700_R9","first-page":"1058","article-title":"Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome.","volume-title":"Nature","year":"2007"},{"key":"2025032622105533700_R10","first-page":"1608","article-title":"STAT3 mutations in the hyper-IgE syndrome.","volume-title":"N. Engl. J. Med.","year":"2007"},{"key":"2025032622105533700_R11","first-page":"2607","article-title":"Roles of STAT3 defined by tissue-specific gene targeting.","volume-title":"Oncogene","year":"2000"},{"key":"2025032622105533700_R12","first-page":"39","article-title":"Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils.","volume-title":"Immunity","year":"1999"},{"key":"2025032622105533700_R13","first-page":"903","article-title":"STAT3 is required for Flt3L-dependent dendritic cell differentiation.","volume-title":"Immunity","year":"2003"},{"key":"2025032622105533700_R14","first-page":"667","article-title":"Class II cytokine receptors and their ligands: key antiviral and inflammatory modulators.","volume-title":"Nat Rev Immunol","year":"2003"},{"key":"2025032622105533700_R15","first-page":"1363","article-title":"Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10.","volume-title":"Nat Immunol.","year":"2007"},{"key":"2025032622105533700_R16","first-page":"335","article-title":"Trophoblast invasion: the role of intracellular cytokine signalling via signal transducer and activator of transcription 3 (STAT3).","volume-title":"Hum Reprod Update","year":"2008"},{"key":"2025032622105533700_R17","first-page":"3801","article-title":"Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality.","volume-title":"Proc. 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Natl. Acad. Sci. USA","year":"1989"},{"key":"2025032622105533700_R38","first-page":"60","article-title":"The role of IL-21 in regulating B-cell function in health and disease.","volume-title":"Immunol. Rev.","year":"2008"},{"key":"2025032622105533700_R39","first-page":"1209","article-title":"Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes.","volume-title":"J. Exp. Med.","year":"1991"},{"key":"2025032622105533700_R40","first-page":"7880","article-title":"General nature of the STAT3-activated anti-inflammatory response.","volume-title":"J. Immunol.","year":"2006"},{"key":"2025032622105533700_R41","first-page":"3354","article-title":"Stat3 in resident macrophages as a repressor protein of inflammatory response.","volume-title":"J. Immunol.","year":"2005"},{"key":"2025032622105533700_R42","first-page":"389","article-title":"Studies with IL-10\u2212\/\u2212 mice: an overview.","volume-title":"J. Leukocyte Biol.","year":"1997"},{"key":"2025032622105533700_R43","first-page":"741","article-title":"Development of dendritic-cell lineages.","volume-title":"Immunity","year":"2007"},{"key":"2025032622105533700_R44","first-page":"1013","article-title":"Job\u2019s syndrome. Recurrent, \u201ccold\u201d, staphylococcal abscesses.","volume-title":"Lancet","year":"1966"},{"key":"2025032622105533700_R45","first-page":"59","article-title":"Extreme hyperimmunoglobulinemia E and undue susceptibility to infection.","volume-title":"Pediatrics","year":"1972"},{"key":"2025032622105533700_R46","first-page":"692","article-title":"Hyper-IgE syndrome with recurrent infections\u2013an autosomal dominant multisystem disorder.","volume-title":"N. Engl. J. Med.","year":"1999"},{"key":"2025032622105533700_R47","first-page":"139","article-title":"The hyper-IgE syndrome.","volume-title":"Clin. Rev. Allergy Immunol.","year":"2001"},{"key":"2025032622105533700_R48","first-page":"277","article-title":"The hyper-IgE syndromes.","volume-title":"Immunol Allergy Clin. North Am.","year":"2008"},{"key":"2025032622105533700_R49","first-page":"26","article-title":"Immunoglobulins in the hyperimmunoglobulin E and recurrent infection (Job\u2019s) syndrome. Deficiency of anti-Staphylococcus aureus immunoglobulin A.","volume-title":"J. Clin. Invest.","year":"1985"},{"key":"2025032622105533700_R50","first-page":"1082","article-title":"Impaired antibody responses in the hyperimmunoglobulin E syndrome.","volume-title":"J. Allergy Clin. Immunol.","year":"1988"},{"key":"2025032622105533700_R51","first-page":"803","article-title":"Antibody responses to protein, polysaccharide, and phi X174 antigens in the hyperimmunoglobulinemia E (hyper-IgE) syndrome.","volume-title":"J. Allergy Clin. Immunol.","year":"1991"},{"key":"2025032622105533700_R52","first-page":"93","article-title":"Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity.","volume-title":"J. Pediatr.","year":"2004"},{"key":"2025032622105533700_R53","first-page":"535","article-title":"The hyper IgE syndrome and mutations in TYK2.","volume-title":"Immunity","year":"2007"},{"key":"2025032622105533700_R54","first-page":"773","article-title":"Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome.","volume-title":"Nature","year":"2008"},{"key":"2025032622105533700_R55","first-page":"1551","article-title":"Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3.","volume-title":"J. Exp. Med.","year":"2008"},{"key":"2025032622105533700_R56","first-page":"1543","article-title":"Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells.","volume-title":"J. Exp. 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Dis.","year":"2004"},{"key":"2025032622105533700_R60","first-page":"639","article-title":"Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells.","volume-title":"Nat. Immunol.","year":"2007"},{"key":"2025032622105533700_R61","first-page":"4615","article-title":"Oncostatin M secreted by skin infiltrating T lymphocytes is a potent keratinocyte activator involved in skin inflammation.","volume-title":"J. Immunol.","year":"2007"},{"key":"2025032622105533700_R62","first-page":"4657","article-title":"Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis.","volume-title":"EMBO J.","year":"1999"},{"key":"2025032622105533700_R63","first-page":"3695","article-title":"IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes.","volume-title":"J. Immunol.","year":"2005"},{"key":"2025032622105533700_R64","first-page":"950","article-title":"Development, cytokine profile and function of human interleukin 17-producing helper T cells.","volume-title":"Nat. Immunol.","year":"2007"},{"key":"2025032622105533700_R65","first-page":"2936","article-title":"Distinct regulation of interleukin-17 in human T helper lymphocytes.","volume-title":"Arthritis Rheum.","year":"2007"},{"key":"2025032622105533700_R66","first-page":"942","article-title":"Interleukins 1\u03b2 and 6 but not transforming growth factor-\u03b2 are essential for the differentiation of interleukin 17-producing human T helper cells.","volume-title":"Nat. Immunol","year":"2007"},{"key":"2025032622105533700_R67","first-page":"641","article-title":"The differentiation of human TH-17 cells requires transforming growth factor-\u03b2 and induction of the nuclear receptor ROR\u03b3t.","volume-title":"Nat. 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Immunol.","year":"2007"},{"key":"2025032622105533700_R72","first-page":"1890","article-title":"Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1992"},{"key":"2025032622105533700_R73","first-page":"106","article-title":"Survival and proliferation factors of normal and malignant plasma cells.","volume-title":"Int. J. Hematol.","year":"2003"},{"key":"2025032622105533700_R74","first-page":"561","article-title":"The role of interleukin-6 in mucosal IgA antibody responses in vivo.","volume-title":"Science","year":"1994"},{"key":"2025032622105533700_R75","first-page":"84","article-title":"Increased in vitro bone resorption by monocytes in the hyper-immunoglobulin E syndrome.","volume-title":"J. Immunol.","year":"1988"},{"key":"2025032622105533700_R76","first-page":"30","article-title":"Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system.","volume-title":"Immunol. Rev.","year":"2005"},{"key":"2025032622105533700_R77","first-page":"800","article-title":"Osteoporosis with increased osteoclastogenesis in hematopoietic cell-specific STAT3-deficient mice.","volume-title":"Biochem. Biophys. Res. 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