Cytokine-Mediated Regulation of Human Lymphocyte Development and Function: Insights from Primary Immunodeficiencies This information is current as Stuart G. Tangye, Simon J. Pelham, Elissa K. Deenick and of October 2, 2021. Cindy S. Ma J Immunol 2017; 199:1949-1958; ; doi: 10.4049/jimmunol.1700842 http://www.jimmunol.org/content/199/6/1949 Downloaded from References This article cites 98 articles, 36 of which you can access for free at: http://www.jimmunol.org/content/199/6/1949.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 2, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology Cytokine-Mediated Regulation of Human Lymphocyte Development and Function: Insights from Primary Immunodeficiencies Stuart G. Tangye, Simon J. Pelham, Elissa K. Deenick, and Cindy S. Ma Cytokine-mediated intracellular signaling pathways are domains of cytokine receptors and, after engagement by spe- fundamental for the development, activation, and dif- cific ligands, phosphorylate key tyrosine residues to pro- ferentiation of lymphocytes. These distinct processes vide docking sites for STATs. Receptor-associated STATs underlie protection against infectious diseases after nat- undergo JAK-mediated phosphorylation, resulting in the for- ural infection with pathogens or immunization, thereby mation of multimers that translocate to the nucleus and bind providing the host with long-lived immunological mem- specific DNA sequences, thereby regulating expression of target ory. In contrast, aberrant cytokine signaling can also genes (1–3). Downloaded from result in conditions of immune dysregulation, such as Approximately 60 different cytokines have been identi- early-onset autoimmunity. Thus, balanced signals pro- fied; these include ILs (IL-1 through IL-38), IFNs, TGFs, and vided by distinct cytokines, and delivered to specific cell members of the TNF superfamily (4). Most cytokines have subsets, are critical for immune homeostasis. The essen- pleiotropic effects on different immune cells; there is also tial roles of cytokines in human immunity have been substantial overlap in their function. Furthermore, ILs and elegantly and repeatedly revealed by the discovery of IFNs can activate numerous JAKs and STATs (5). In vivo http://www.jimmunol.org/ individuals with mutations in cytokine ligands, recep- mouse models and in vitro analyses have identified the key tors, and downstream transcription factors that cause biology of cytokines and informed us that cytokines are primary immunodeficiency or autoimmune conditions. critical for lymphocyte development and differentiation. However, the nonredundant functions of specific cytokines in In this article, we review how the discovery and char- the setting of natural infection and immune dysregulation in acterization of such individuals has identified nonre- humans are constantly being elegantly revealed by the dis- dundant, and often highly specialized, functions of covery and characterization of individuals with monogenic specific cytokines and immune cell subsets in human mutations in cytokine signaling pathways that manifest as by guest on October 2, 2021 lymphocyte biology, host defense against infections, immunodeficient and/or autoimmune states (3, 6–8). Cur- and immune regulation. The Journal of Immunology, rently, loss-of-expression or loss-of-function (LOF) mutations 2017, 199: 1949–1958. have been identified in genes encoding cytokines (IL10, IL17F, IL12B, IL21), cytokine receptors (IL2RA, IL2RG, IL7RA, IL10RA, IL10RB, IL11RA, IL12RB1, IL17RA, IL7RC, he generation of lymphocytes from stem cell pre- IL21R, IFNGR1, IFNGR2, IFNAR2),JAKs(JAK1, JAK3, cursors in bone marrow, thymus, and fetal tissues, and TYK2), transcription factors activated by specific cytokines T their subsequent differentiation into effector cells, (STAT1, STAT2, STAT3, STAT5B), and transcription factors requires signals provided by a myriad of surface receptors, that regulate lymphocyte fate (FOXP3, RORC), resulting in including clonotypic T and B cell Ag receptors and those impaired development or effector function of different im- belonging to Ig and TNFR superfamilies, chemokine receptors mune cells (Table I) (6–8). Remarkably, activating or gain-of- and cytokine receptors. The biological effects of many cyto- function (GOF) mutations have also been identified in some of kines are mediated by JAK/STAT signaling pathways (1–3). these genes—JAK1 (9), STAT1 (10, 11), STAT3 (12–14), and Four JAKs (JAK1, JAK2, JAK3, and Tyk2) and seven STATs STAT5B (15) (Table I)—indicating that dysregulated activity (STAT1, 2, 3, 4, 5a, 5b, and 6) have been identified in mam- of key transcription factors can also be deleterious to immune malian genomes (1, 2). JAKs associate with the cytoplasmic cell function, and thus human health. In this review, we provide Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Address correspondence and reprint requests to Dr. Stuart G. Tangye, Immunology Wales 2010, Australia; and St. Vincent’s Clinical School, University of New South Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Wales, Sydney, New South Wales 2010, Australia NSW 2010, Australia. E-mail address: [email protected] ORCID: 0000-0002-5360-5180 (S.G.T.). Abbreviations used in this article: AD, autosomal dominant; AR, autosomal recessive; gc, g-chain; CMC, chronic mucocutaneous candidiasis; cTfh, circulating Tfh; GC, Received for publication June 12, 2017. Accepted for publication June 22, 2017. germinal center; GOF, gain-of-function; ILC, innate lymphoid cell; iNKT, invariant This work was supported by research grants and fellowships awarded by the National NKT; IPEX, immune dysregulation, polyendocrinopathy, and enteropathy, X-linked; Health and Medical Research Council of Australia, the Office of Health and Medical LOF, loss-of-function; MAIT, mucosal-associated invariant T; MSMD, Mendelian sus- Research of the New South Wales State Government, and the Jeffrey Modell Foundation ceptibility to mycobacterial disease; PID, primary immunodeficiency; Tfh, T follicular (to the laboratories of S.G.T., C.S.M., and E.K.D.) and by an Australian Postgraduate helper; Treg, regulatory T cell; X-SCID, X-linked SCID. Award from the University of New South Wales, Australia (to S.J.P.). Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$35.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700842 1950 BRIEF REVIEWS: GENE MUTATIONS AFFECTING HUMAN LYMPHOCYTES an overview of how the study of rare “experiments of nature” switching, and production of large amounts of all Ig isotypes has delineated fundamental and unique functions of cytokines, by naive, memory, and GC B cells (33, 35, 36) (Fig. 1). This and the requirements for their associated signaling pathways, in is due to IL-21 inducing the molecular machinery required human lymphocyte biology, and how these findings reveal for isotype switching (AICDA, encoding activation-induced mechanisms of disease pathogenesis and are impacting the di- cytidine deaminase) and plasma cell differentiation (PRDM1 agnosis, management, and treatment of individuals with [Blimp-1], XBP1; Fig. 1) (33, 34, 37). The receptor for IL-21 monogenic immunological dyscrasias. comprises IL-21R and gc (22). Binding of IL-21 to the IL-21R activates JAK1 and JAK3, with subsequent phosphorylation Cytokines utilizing the IL-2 common g-chain are required for the of STAT1, STAT3, and STAT5 (5, 22, 37). Remarkably, development of human T cells and NK cells, but not B cells pathogenic mutations have been identified at each stage of A seminal discovery in immunology was the finding that the IL-21 signaling, and studies of these affected individuals g-chain (gc) of the IL-2R was also a component of receptor have revealed a key role for IL-21 in human B cell differ- complexes for IL-4 and IL-7 (16–19). With the discovery of entiationinvivo. additional cytokines, IL-2Rgc was found to also be a com- Dominant negative LOF mutations in STAT3 cause the ponent of the receptors for IL-9 (20), IL-15 (21), and IL-21 multisystemic disorder autosomal dominant (AD) hyper-IgE (22). Mutations in IL2RG encoding gc cause X-linked SCID syndrome (38, 39). In addition to susceptibility to infections (X-SCID) (23), which is characterized by extreme suscepti- with Staphylococcus and Candida, these patients have defects bility to infection with almost all pathogens (24). The cellular in Ag-specific Ab responses (8, 40, 41). Consistent with this, basis for X-SCID is the absence of T cells and NK cells. there are marked reductions in memory B cells in these pa- Downloaded from Remarkably, B cells develop in X-SCID, but because of the tients, and their naive