PIR-B Regulates CD4+ IL17a+ T-Cell Survival and Restricts T-Cell-Dependent Intestinal Inflammatory Responses

Abstract

Background & aims: CD4⁺ T cells are regulated by activating and inhibitory cues, and dysregulation of these proper regulatory inputs predisposes these cells 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.

Methods: We used Il10^-/- spontaneous and CD4⁺CD45RB^hi T-cell transfer models of colitis with PIR-B-deficient (Pirb^-/-) mice. Flow cytometry, Western blot, and RNA sequencing analysis was performed on wild-type and Pirb^-/- CD4⁺ T cells. In silico analyses were performed on RNA sequencing data set of ileal biopsy samples from pediatric CD and non-inflammatory bowel disease patients and sorted human memory CD4⁺ T cells.

Results: We identified PIR-B expression on memory CD4⁺ interleukin (IL)17a⁺ cells. We show that PIR-B regulates CD4⁺ T-helper 17 cell (Th17)-dependent chronic intestinal inflammatory responses and the development of colitis. Mechanistically, we show that the PIR-B- Src-homology region 2 domain-containing phosphatase-1/2 axis tempers mammalian target of rapamycin complex 1 signaling and mammalian target of rapamycin complex 1-dependent caspase-3/7 apoptosis, resulting in CD4⁺ IL17a⁺ cell survival. In silico analyses showed enrichment of transcriptional signatures for Th17 cells (RORC, RORA, and IL17A) and tissue resident memory (HOBIT, IL7R, and BLIMP1) networks in PIR-B⁺ murine CD4⁺ T cells and human CD4⁺ T cells that express the human homologue leukocyte immunoglobulin-like receptor subfamily B member 3 (LILRB3). High levels of LILRB3 expression were associated strongly with mucosal injury and a proinflammatory Th17 signature, and this signature was restricted to a treatment-naïve, severe pediatric CD population.

Conclusions: Our findings show an intrinsic role for PIR-B/LILRB3 in the regulation of CD4⁺ IL17a⁺ T-cell pathogenic memory responses.

Keywords: CD4(+) T Cells; Inflammatory Bowel Disease; Interleukin 17; Paired Immunoglobulin Receptor.