TY - JOUR
T1 - PIR-B Regulates CD4+ IL17a+ T-Cell Survival and Restricts T-Cell–Dependent Intestinal Inflammatory Responses
AU - Uddin, Jazib
AU - Tomar, Sunil
AU - Sharma, Ankit
AU - Waggoner, Lisa
AU - Ganesan, Varsha
AU - Marella, Sahiti
AU - Yang, Yanfen
AU - Noah, Taeko
AU - Vanoni, Simone
AU - Patterson, Andrew
AU - Zeng, Chang
AU - Foster, Paul S.
AU - Newberry, Rodney
AU - Bishu, Shrinivas
AU - Kao, John Y.
AU - Rosen, Michael J.
AU - Denson, Lee
AU - King, Philip D.
AU - Hoebe, Kasper
AU - Divanovic, Senad
AU - Munitz, Ariel
AU - Hogan, Simon P.
N1 - Funding Information:
Funding Supported by National Institutes of Health grants DK073553, DK090119, DK125007, DK099222, AI138177, AI112626, and AI007413; Food Allergy Research and Education; Department of Defense grant W81XWH-15-1-051730; M-FARA; and the Mary H. Weiser Food Allergy Center (S.P.H.).
Publisher Copyright:
© 2021 The Authors
PY - 2021/1
Y1 - 2021/1
N2 - 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+CD45RBhi 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.
AB - 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+CD45RBhi 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.
KW - CD4 T Cells
KW - Inflammatory Bowel Disease
KW - Interleukin 17
KW - Paired Immunoglobulin Receptor
UR - http://www.scopus.com/inward/record.url?scp=85116304085&partnerID=8YFLogxK
U2 - 10.1016/j.jcmgh.2021.06.013
DO - 10.1016/j.jcmgh.2021.06.013
M3 - Article
C2 - 34242819
AN - SCOPUS:85116304085
SN - 2352-345X
VL - 12
SP - 1479
EP - 1502
JO - CMGH
JF - CMGH
IS - 4
ER -