Checkpoint Receptor TIGIT Expressed on Tim-1+ B Cells Regulates Tissue Inflammation
Sheng Xiao, Lloyd Bod, Nathalie Pochet, Savithri B. Kota, Dan Hu, Asaf Madi, Jessica Kilpatrick, Jingwen Shi, Allen W. Ho, Huiyuan Zhang, Raymond A. Sobel, Howard L. Weiner, Terry B. Strom, Francisco J. Quintana, Nicole Joller, Vijay K. Kuchroo
Abstract
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.