PIR-B Regulates CD4+ IL17a+ T-Cell Survival and Restricts T-Cell–Dependent Intestinal Inflammatory Responses
| Autor: | Kasper Hoebe, Shrinivas Bishu, John Y. Kao, Varsha Ganesan, Ankit Sharma, Yanfen Yang, Chang Zeng, Rodney D. Newberry, Sahiti Marella, Simon P. Hogan, Philip D. King, Ariel Munitz, Jazib Uddin, Taeko K. Noah, Lee A. Denson, Andrew R. Patterson, Simone Vanoni, Lisa Waggoner, Senad Divanovic, Paul S. Foster, Michael J. Rosen, S. M. S. Tomar |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
CD4+ T Cells
mLN mesenteric lymph node Th T-helper cell Cell RC799-869 mTORC1 Paired Immunoglobulin Receptor PIR-B paired immunoglobulin-like receptor B GAP GTPase-activating protein Mice PCR polymerase chain reaction ERK extracellular signal-regulated kinase GTP guanosine triphosphate RAR-related orphan receptor gamma T-Lymphocyte Subsets Interleukin 17 DEG differentially expressed gene LP lamina propria Intestinal Mucosa Receptors Immunologic Receptor Original Research GFP green fluorescent protein Mice Knockout TNF tumor necrosis factor IBD inflammatory bowel disease Interleukin-17 Gastroenterology DU deep ulcer ILC innate lymphoid cell mTORC1 mammalian target of rapamycin complex 1 Diseases of the digestive system. Gastroenterology Colitis Immunohistochemistry mRNA messenger RNA Interleukin-10 iCD ileal involvement Crohn’s disease medicine.anatomical_structure LILRB3 leukocyte immunoglobulin-like receptor subfamily B member 3 Disease Susceptibility SHP Src-homology region 2 domain-containing phosphatase Signal Transduction TSC tuberous sclerosis Cell Survival T cell Biology Proinflammatory cytokine Immunophenotyping Immunomodulation p-ERK phosphorylated extracellular signal-regulated kinase cCD colonic-only involvement Crohn’s disease medicine CD Crohn’s disease Animals IFN interferon Interleukin-7 receptor RPKM reads per kb of transcript per million mapped reads Hepatology Gene Expression Profiling Inflammatory Bowel Disease ITIM immunoreceptor tyrosine-based inhibitory motif Inflammatory Bowel Diseases Molecular biology WT wild-type IL interleukin Disease Models Animal Gene Expression Regulation TRM tissue resident memory Immunologic Memory Biomarkers Q quartile |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 4, Pp 1479-1502 (2021) |
| ISSN: | 2352-345X |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
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