PIR-B Regulates CD4+ IL17a+ T-Cell Survival and Restricts T-Cell–Dependent Intestinal Inflammatory Responses
| العنوان: | PIR-B Regulates CD4+ IL17a+ T-Cell Survival and Restricts T-Cell–Dependent Intestinal Inflammatory Responses |
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| المؤلفون: | 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 |
| المصدر: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 4, Pp 1479-1502 (2021) |
| بيانات النشر: | Elsevier, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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 |
| اللغة: | English |
| تدمد: | 2352-345X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f5bc9234d68120dd2171e099da6a99f4 http://europepmc.org/articles/PMC8531983 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....f5bc9234d68120dd2171e099da6a99f4 |
| قاعدة البيانات: | OpenAIRE |
Full Text via ClinicalKey | تدمد: | 2352345X |
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