Checkpoint Receptor TIGIT Expressed on Tim-1+ B Cells Regulates Tissue Inflammation
Sheng Xiao,
Lloyd Bod,
Nathalie Pochet,
Savithri Balasubramanian Kota,
Dan Hu,
Asaf Madi,
Jessica Kilpatrick,
Jingwen Shi,
Allen Ho,
Huiyuan Zhang,
Raymond Sobel,
Howard L. Weiner,
Terry B. Strom,
Francisco J. Quintana,
Nicole Joller,
Vijay K. Kuchroo
Affiliations
Sheng Xiao
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA; Corresponding author
Lloyd Bod
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA
Nathalie Pochet
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA
Savithri Balasubramanian Kota
Renal Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA
Dan Hu
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA
Asaf Madi
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA
Jessica Kilpatrick
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA
Jingwen Shi
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA
Allen Ho
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA
Huiyuan Zhang
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA
Raymond Sobel
Palo Alto Veteran’s Administration Health Care System and Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
Howard L. Weiner
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA
Terry B. Strom
Transplant Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA
Francisco J. Quintana
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA
Nicole Joller
Institute of Experimental Immunology, University of Zurich, Zurich 8057, Switzerland
Vijay K. Kuchroo
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA; Corresponding author
Summary: Tim-1, a phosphatidylserine receptor expressed on B cells, induces interleukin 10 (IL-10) production by sensing apoptotic cells. Here we show that mice with B cell-specific Tim-1 deletion develop tissue inflammation in multiple organs including spontaneous paralysis with inflammation in the central nervous system (CNS). Transcriptomic analysis demonstrates that besides IL-10, Tim-1+ B cells also differentially express a number of co-inhibitory checkpoint receptors including TIGIT. Mice with B cell-specific TIGIT deletion develop spontaneous paralysis with CNS inflammation, but with limited inflammation in other organs. Our findings suggest that Tim-1+ B cells are essential for maintaining self-tolerance and restraining tissue inflammation, and that Tim-1 signaling-dependent TIGIT expression on B cells is essential for maintaining CNS-specific tolerance. A possible critical role of aryl hydrocarbon receptor (AhR) in regulating the B cell function is discussed, as we find that AhR is among the preferentially expressed transcription factors in Tim-1+ B cells and regulates their TIGIT and IL-10 expression.
