Cbl-b restrains priming of pathogenic Th17 cells via the inhibition of IL-6 production by macrophages
Qiuming Zeng,
Na Tang,
Yilei Ma,
Hui Guo,
Yixia Zhao,
Rong Tang,
Chengkai Yan,
Song Ouyang,
Wallace Y. Langdon,
Huan Yang,
Matthew C. O’Brien,
Jian Zhang
Affiliations
Qiuming Zeng
Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA; Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA; Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
Na Tang
Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA; Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA
Yilei Ma
Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
Hui Guo
Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA; Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA
Yixia Zhao
Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA; Department of Cardiology, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
Rong Tang
Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA; Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
Chengkai Yan
Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
Song Ouyang
Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA; Department of Neurology, The First Hospital of Changsha, Changsha, Hunan, P.R. China
Wallace Y. Langdon
School of Biomedical Sciences, University of Western Australia, Perth, Australia
Huan Yang
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
Matthew C. O’Brien
Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
Jian Zhang
Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA; Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA; Corresponding author
Summary: E3 ubiquitin ligase Cbl-b is involved in the maintenance of a balance between immunity and tolerance. Mice lacking Cbl-b are highly susceptible to experimental autoimmune encephalomyelitis (EAE), a Th17-mediated autoimmune disease. However, how Cbl-b regulates Th17 cell responses remains unclear. In this study, utilizing adoptive transfer and cell type-specific Cblb knockout strains, we show that Cbl-b expression in macrophages, but not T cells or dendritic cells (DCs), restrains the generation of pathogenic Th17 cells and the development of EAE. Cbl-b inhibits IL-6 production by macrophages that is induced by signaling from CARD9-dependent C-type lectin receptor (CLR) pathways, which directs T cells to generate pathogenic Th17 cells. Therefore, our data unveil a previously unappreciated function for Cbl-b in the regulation of pathogenic Th17 responses.
