title: Conditional Deletion of TAK1 in T Cells Reveals a Pivotal Role of TCRαβ+ Intraepithelial Lymphocytes in Preventing Lymphopenia-Associated Colitis.
abstract: The kinase TAK is required for the development of conventional and regulatory T cells. We previously reported that mice with conditional deletion of TAK1 in T cells (Lck-cre:TAK1fl/fl mice) exhibited severe T lymphopenia, and were nevertheless predisposed to spontaneous colitis with unknown etiology. Here we focused on the immunopathological mechanism in colitic Lck-cre:TAK1fl/fl mice. We found that 'leaky' CD4+ T cells retaining TAK1 acquired inflammatory phenotypes that contribute to disease onset in Lck-cre:TAK1fl/fl mice. Furthermore, the gut microbiota-triggered signaling was also a key event leading to the pathogenesis. We discovered that Lck-cre:TAK1fl/fl mice were almost completely devoid of TCRαβ+CD8α+ intestinal intraepithelial lymphocytes (IELs) and this was largely due to the developmental defect of the thymic precursors by TAK1 deficiency. Remarkably, transfer of TCRαβ+CD8α+ IELs from wild-type mice ameliorated colitis in Lck-cre:TAK1fl/fl mice. Taken together, our current study highlighted the emerging role of TAK1 in configuring the gut-specialized T cell subset, which regulates mucosal homeostasis under lymphopenic conditions.
authors.affiliation: Department of Molecular and Cellular Immunology, Shinshu University School of Medicine, Nagano, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Sanjo
authors.affiliation: Department of Molecular and Cellular Immunology, Shinshu University School of Medicine, Nagano, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Tokumaru
authors.affiliation: Laboratory of Host Defense, Immunology Frontier Research Center, Osaka University, Osaka, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Department of Molecular and Cellular Immunology, Shinshu University School of Medicine, Nagano, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Taki
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D003092:Colitis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D008231:Lymphopenia / Q000150:complications*; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009093:Mucus / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; D020930:MAP Kinase Kinase Kinases; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051192:Receptors, Pattern Recognition; D000099151:MAP Kinase Kinase Kinase 7