title: 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.
abstract: 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 recombination and plasma cell differentiation. IRF4 function in T helper cells can be modulated 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 selectively control the ability of IRF4 to regulate IL-21 responsiveness in a stage-specific manner. 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 productive T-B cell interactions.
authors.affiliation: Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Partha S
authors.initials: PS
authors.lastname: Biswas
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
authors.forename: Roslynn A
authors.initials: RA
authors.lastname: Stirzaker
authors.forename: Varsha
authors.initials: V
authors.lastname: Kumar
authors.forename: Rolf
authors.initials: R
authors.lastname: Jessberger
authors.forename: Theresa T
authors.initials: TT
authors.lastname: Lu
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.forename: Alessandra B
authors.initials: AB
authors.lastname: Pernis
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000276:immunology / Q000517:prevention & control; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000276:immunology*; D007378:Interleukins / Q000096:biosynthesis; D008211:Lymphocyte Cooperation / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D000098546:Interleukin-21; D000099218:Interferon Regulatory Factor-4
chemical_list: D001323:Autoantibodies; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D050835:Interferon Regulatory Factors; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D000098546:Interleukin-21; D000099218:Interferon Regulatory Factor-4; C473249:Def6 protein, mouse; C113365:Swap70 protein, mouse