e n i c i d e M l a t n e m i r e p x E f o l a n r u o J e h T CORRESPONDENCE James A Johnston: jim.johnston@qub.ac.uk OR Adrien Kissenpfennig: a.kissenpfennig@qub.ac.uk Abbreviations used: AD, atopic dermatitis; AHR, airway hyper- responsiveness; RL, lung resis- tance; SEA, schistosome soluble egg antigen; SOCS, suppressor of cytokine signaling. The Rockefeller University Press $30.00 J. Exp. Med. Vol. 208 No. 7 1523-1531 www.jem.org/cgi/doi/10.1084/jem.20101167 A r t i c l e SOCS2 regulates T helper type 2 differentiation and the generation of type 2 allergic responses Camille A. Knosp,1 Helen P. Carroll,1 Joanne Elliott,1 Sean P. Saunders,2 Hendrik J. Nel,2 Sylvie Amu,2 Joanne C. Pratt,3 Shaun Spence,1 Emma Doran,1 Nicola Cooke,1 Ruaidhri Jackson,1 Jonathan Swift,1 Denise C. Fitzgerald,1 Liam G. Heaney,1 Padraic G. Fallon,2,4 Adrien Kissenpfennig,1 and James A. Johnston1 1The Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University, Belfast BT9 7BL, Northern Ireland 2Institute of Molecular Medicine, St. James’s Hospital, Trinity College Dublin, Dublin 8, Ireland 3Franklin W. Olin College of Engineering, Needham, MA 02492 4National Children’s Research Centre, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland The incidence of allergy and asthma in developed countries is on the increase and this trend looks likely to continue. CD4+ T helper 2 (Th2) cells are major drivers of these diseases and their commitment is controlled by cytokines such as interleukin 4, which are in turn regu- lated by the suppressor of cytokine signaling (SOCS) proteins. We report that SOCS2/ CD4+ T cells show markedly enhanced Th2 differentiation. SOCS2/ mice, as well as RAG- 1/ mice transferred with SOCS2/ CD4+ T cells, exhibit elevated type 2 responses after helminth antigen challenge. Moreover, in in vivo models of atopic dermatitis and allergen- induced airway inflammation, SOCS2/ mice show significantly elevated IgE, eosinophilia, type 2 responses, and inflammatory pathology relative to wild-type mice. Finally, after T cell activation, markedly enhanced STAT6 and STAT5 phosphorylation is observed in SOCS2/ T cells, whereas STAT3 phosphorylation is blunted. Thus, we provide the first evidence that SOCS2 plays an important role in regulating Th2 cell expansion and develop- ment of the type 2 allergic responses. Allergic diseases such as atopic dermatitis (AD) and asthma are orchestrated and enhanced by CD4+ Th2 lymphocytes and the cytokines they produce, namely IL-4, IL-5, and IL-13. These type two cytokines drive elevated serum IgE and infiltration of Th2 cells, eosinophils, and baso- phils, which have been observed in patients with asthma and AD (Venge et al., 1996; Sudowe et al., 2000;Walter et al., 2001; Nakajima and Takatsu, 2007). IL-4 and IL-13 mediate their responses by activating JAK kinases and STAT6, a transcription factor responsible for activating many allergy-associated genes (Kato and Schleimer, 2007). The suppressor of cytokine signaling (SOCS) family of proteins is a key controller of cytokine responses,which can down-regulate specific cyto- kine signals and consequently modify the im- mune response (Alexander, 2002; Croker et al., 2008;Dimitriou et al.,2008).SOCS1 and SOCS3 have been shown to influence the Th1/Th2 bal- ance (Kubo and Inoue, 2006; Yoshimura et al., 2007; Palmer and Restifo, 2009). In particular, SOCS3 expression correlates with the severity of asthma and AD, as well as serum IgE levels in patients with allergy (Seki et al., 2003).Although SOCS2 is expressed in activated CD4+T cells and its expression can regulate IL-2 and IL-3 signals (Tannahill et al., 2005), no role for SOCS2 in CD4+ T cell differentiation has yet been defined. In this paper, we demonstrate that activated SOCS2/ CD4+ T cells show significantly higher IL-4, IL-5, and IL-13 production and Th2 differentiation and that they had elevated SOCS3- and IL-4–induced STAT6 but blunted IL-6–induced STAT3 phosphorylation. More- over, SOCS2/ mice were highly susceptible to AD with a marked eosinophilic infiltrate and, after helminth antigen challenge, produced © 2011 Knosp et al. This article is distributed under the terms of an Attribution– Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/ by-nc-sa/3.0/). 1523