Uma Chandrasekaran1, Woelsung Yi1, Sanjay Gupta1, Chien-Huan Weng2, Eugenia Giannopoulou3, Yurii Chinenov1, Rolf Jessberger4, Casey T Weaver5, Govind Bhagat6, Alessandra B Pernis7. 1. Hospital for Special Surgery, New York, New York. 2. Hospital for Special Surgery and Weill Cornell Graduate School of Medical Sciences, New York, New York. 3. Hospital for Special Surgery, New York, and New York City College of Technology, City University of New York, Brooklyn, New York. 4. Dresden University of Technology, Dresden, Germany. 5. University of Alabama at Birmingham. 6. Columbia University Medical Center and New York Presbyterian Hospital, New York, New York. 7. Hospital for Special Surgery, Weill Cornell Graduate School of Medical Sciences, and Weill Cornell Medicine, Cornell University, New York, New York.
Abstract
OBJECTIVE: Treg cells need to acquire an effector phenotype to function in settings of inflammation. Whether effector Treg cells can limit disease severity in lupus is unknown. Interferon regulatory factor 4 (IRF-4) is an essential controller of effector Treg cells and regulates their ability to express interleukin-10 (IL-10). In non-Treg cells, IRF-4 activity is modulated by interactions with DEF-6 and its homolog switch-associated protein 70 (SWAP-70). Although mice lacking both DEF-6 and SWAP-70 (double-knockout [DKO] mice) develop lupus, they display normal survival, suggesting that in DKO mice, Treg cells can moderate disease development. The purpose of this study was to investigate whether Treg cells from DKO mice have an increased capacity to become effector Treg cells due to the ability of DEF-6 and SWAP-70 to restrain IRF-4 activity. METHODS: Treg cells were evaluated by fluorescence-activated cell sorting. The B lymphocyte-induced maturation protein 1 (BLIMP-1)/IL-10 axis was assessed by crossing DKO mice with BLIMP-1-YFP-10BiT dual-reporter mice. Deletion of IRF-4 in Treg cells from DKO mice was achieved by generating FoxP3(Cre) IRF-4(fl/fl) DKO mice. RESULTS: The concomitant absence of DEF-6 and SWAP-70 led to increased numbers of Treg cells, which acquired an effector phenotype in a cell-intrinsic manner. In addition, Treg cells from DKO mice exhibited enhanced expression of the BLIMP-1/IL-10 axis. Notably, DKO effector Treg cells survived and expanded as disease progressed. The accumulation of Treg cells from DKO mice was associated with the up-regulation of genes controlling autophagy. IRF-4 was required for the expansion and function of effector Treg cells from DKO mice. CONCLUSION: This study revealed the existence of mechanisms that, by acting on IRF-4, can fine-tune the function and survival of effector Treg cells in lupus. These findings suggest that the existence of a powerful effector Treg cell compartment that successfully survives in an unfavorable inflammatory environment could limit disease development.
OBJECTIVE: Treg cells need to acquire an effector phenotype to function in settings of inflammation. Whether effector Treg cells can limit disease severity in lupus is unknown. Interferon regulatory factor 4 (IRF-4) is an essential controller of effector Treg cells and regulates their ability to express interleukin-10 (IL-10). In non-Treg cells, IRF-4 activity is modulated by interactions with DEF-6 and its homolog switch-associated protein 70 (SWAP-70). Although mice lacking both DEF-6 and SWAP-70 (double-knockout [DKO] mice) develop lupus, they display normal survival, suggesting that in DKO mice, Treg cells can moderate disease development. The purpose of this study was to investigate whether Treg cells from DKO mice have an increased capacity to become effector Treg cells due to the ability of DEF-6 and SWAP-70 to restrain IRF-4 activity. METHODS: Treg cells were evaluated by fluorescence-activated cell sorting. The B lymphocyte-induced maturation protein 1 (BLIMP-1)/IL-10 axis was assessed by crossing DKO mice with BLIMP-1-YFP-10BiT dual-reporter mice. Deletion of IRF-4 in Treg cells from DKO mice was achieved by generating FoxP3(Cre) IRF-4(fl/fl) DKO mice. RESULTS: The concomitant absence of DEF-6 and SWAP-70 led to increased numbers of Treg cells, which acquired an effector phenotype in a cell-intrinsic manner. In addition, Treg cells from DKO mice exhibited enhanced expression of the BLIMP-1/IL-10 axis. Notably, DKO effector Treg cells survived and expanded as disease progressed. The accumulation of Treg cells from DKO mice was associated with the up-regulation of genes controlling autophagy. IRF-4 was required for the expansion and function of effector Treg cells from DKO mice. CONCLUSION: This study revealed the existence of mechanisms that, by acting on IRF-4, can fine-tune the function and survival of effector Treg cells in lupus. These findings suggest that the existence of a powerful effector Treg cell compartment that successfully survives in an unfavorable inflammatory environment could limit disease development.
Authors: J Christoph Vahl; Christoph Drees; Klaus Heger; Sylvia Heink; Julius C Fischer; Jelena Nedjic; Naganari Ohkura; Hiromasa Morikawa; Hendrik Poeck; Sonja Schallenberg; David Rieß; Marco Y Hein; Thorsten Buch; Bojan Polic; Anne Schönle; Robert Zeiser; Annette Schmitt-Gräff; Karsten Kretschmer; Ludger Klein; Thomas Korn; Shimon Sakaguchi; Marc Schmidt-Supprian Journal: Immunity Date: 2014-11-06 Impact factor: 31.745
Authors: Jean-François Marquis; Oxana Kapoustina; David Langlais; Rebecca Ruddy; Catherine Rosa Dufour; Bae-Hoon Kim; John D MacMicking; Vincent Giguère; Philippe Gros Journal: PLoS Genet Date: 2011-06-23 Impact factor: 5.917