Cellular and molecular gastroenterology and hepatology | 2021
PIR-B Regulates CD4+ IL-17a+ T Cell Survival and Restricts T-cell Dependent Intestinal Inflammatory Responses.
Abstract
BACKGROUND & AIMS\nCD4+ T cells are regulated by activating and inhibitory cues and dysregulation of these proper regulatory inputs predisposes to aberrant inflammation and exacerbation of disease. We investigated the role of the inhibitory receptor, paired immunoglobulin-like receptor B (PIR-B) in the regulation of the CD4+ T-cell inflammatory response and exacerbation of the colitic phenotype.\n\n\nMETHODS\nWe employed Il10-/- spontaneous and CD4+CD45RBhi T cell transfer models of colitis with PIR-B (Pirb-/-) deficient mice. Flow cytometry, western blot, RNA-seq analysis was performed on wild type and Pirb-/- CD4+ T cells. In silico analyses were performed on RNA-seq dataset of ileal biopsy samples from pediatric CD and non-IBD patients and sorted human memory CD4+ T cells.\n\n\nRESULTS\nWe identified PIR-B expression on memory CD4+ IL-17a+ cells. We show that PIR-B regulates CD4+ Th17-dependent chronic intestinal inflammatory responses and development of colitis. Mechanistically, we reveal that the PIR-B-SHP-1/2 axis tempers mTORC1 signaling and mTORC1-dependent Caspase-3/7 apoptosis resulting in CD4+ IL-17a+ cell survival. In silico analyses reveal enrichment of transcriptional signatures for Th17 cells (RORC, RORA, IL-17A) and tissue resident memory (TRM) (HOBIT, IL7R and BLIMP1) networks in PIR-B+ murine CD4+ T cells and human CD4+ T cells that express the human homologue, LILRB3. High levels of LILRB3 expression were strongly associated with mucosal injury and a proinflammatory Th17-signature, and this signature was restricted to a treatment-naïve severe pediatric CD population.\n\n\nCONCLUSIONS\nOur findings demonstrate an intrinsic role for PIR-B/LILRB3 in the regulation of CD4+ IL-17a+ T cell pathogenic memory responses.