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 A r t i c l e Dual regulation of IRF4 function in T and B cells is required for the coordination of T–B cell interactions and the prevention of autoimmunity Partha S. Biswas,1 Sanjay Gupta,1 Roslynn A. Stirzaker,1 Varsha Kumar,1 Rolf Jessberger,5 Theresa T. Lu,1,2,4 Govind Bhagat,6 and Alessandra B. Pernis1,2,3 1Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021 2Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065 3Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065 4Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY 10065 5Institute of Physiological Chemistry, Dresden University of Technology, 01307 Dresden, Germany 6Department of Pathology and Cell Biology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY 10032 CORRESPONDENCE Alessandra Pernis: pernisa@hss.edu Abbreviations used: AID, acti- vation-induced cytidine deami- nase; ChIP, chromatin immunoprecipitation; DKO, double KO; GC, germinal cen- ter; IRF4, interferon regulatory factor 4; SLE, systemic lupus erythematosus; SWAP-70, SWAP switching B-cell com- plex 70 kD subunit; Tfh, fol- licular T helper cell. The Rockefeller University Press $30.00 J. Exp. Med. Vol. 209 No. 3 581-596 www.jem.org/cgi/doi/10.1084/jem.20111195 Effective humoral responses to protein antigens require the precise execution of carefully timed differentiation programs in both T and B cell compartments. Disturbances in this process underlie the pathogenesis of many autoimmune disorders, including systemic lupus erythematosus (SLE). Interferon regulatory factor 4 (IRF4) is induced upon the activation of T and B cells and serves critical functions. In CD4+ T helper cells, IRF4 plays an essential role in the regulation of IL-21 production, whereas in B cells it controls class switch re- combination and plasma cell differentiation. IRF4 function in T helper cells can be modu- lated by its interaction with regulatory protein DEF6, a molecule that shares a high degree of homology with only one other protein, SWAP-70. Here, we demonstrate that on a C57BL/6 background the absence of both DEF6 and SWAP-70 leads to the development of a lupus-like disease in female mice, marked by simultaneous deregulation of CD4+ T cell IL-21 production and increased IL-21 B cell responsiveness. We furthermore show that DEF6 and SWAP-70 are differentially used at distinct stages of B cell differentiation to selec- tively control the ability of IRF4 to regulate IL-21 responsiveness in a stage-specific man- ner. Collectively, these data provide novel insights into the mechanisms that normally couple and coordinately regulate T and B cell responses to ensure tight control of produc- tive T–B cell interactions. Effective collaboration between T and B cells is essential for the production of high-affinity antibodies, which confer long-lasting immu- nity against offending pathogens (McHeyzer- Williams et al., 2009; Elgueta et al., 2010). T cell help for B cells requires the precisely orches- trated antigen-driven repositioning of T and B cells within secondary lymphoid organs (Cyster, 2010; Goodnow et al., 2010). After activation by dendritic cells, T cells migrate to the bound- ary between the T cell zone and B cell follicles, P.S. Biswas’s current address is Division of Rheumatology and Clinical Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA. where the earliest encounter with antigen- bearing B cells occurs. After interaction with T cells, B cells can migrate to extrafollicular areas, where they become short-lived plasmablasts, or they can remain in the follicle and form germi- nal centers (GCs), the crucial anatomical sites where somatic hypermutation occurs. Upon further productive interactions with special- ized T helper cells within the GCs, appropriately © 2012 Biswas 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–Noncommer- cial–Share Alike 3.0 Unported license, as described at http://creativecommons .org/licenses/by-nc-sa/3.0/). 581