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Insights into the Role of STAT3 in Human Lymphocyte Differentiation as Revealed by the Hyper-IgE Syndrome¹

Stuart G. Tangye^2,3,*, Matthew C. Cook^2,, and David A. Fulcher^2,

^* Immunology and Inflammation Program, Garvan Institute of Medical Research, Darlinghurst, Australia; John Curtin School of Medical Research, Australian National University, Canberra, Australia; Department of Immunology, The Canberra Hospital, Woden, Australia; and Department of Immunology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, Australia

"Experiments of nature" 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a program grant (to S.G.T. and M.C.C.), a project grant (to D.A.F. and S.G.T.), and a senior research fellowship (to S.G.T.) awarded by the National Health and Medical Research Council of Australia.

² S.G.T., M.C.C., and D.A.F. contributed equally to this review.

³ Address correspondence and reprint requests to Dr. Stuart Tangye, Immunology and Inflammation Department, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst 2010, New South Wales, Australia. E-mail address: s.tangye{at}garvan.org.au

⁴ Abbreviations used in this paper: SOCS, suppressor of cytokine signaling; AD, autosomal dominant; AR, autosomal recessive; DC, dendritic cell; HIES, hyper-IgE syndrome; PC, plasma cell; ROR, retinoic acid-related orphan nuclear receptor.