title: Temporal Expression of Bim Limits the Development of Agonist-Selected Thymocytes and Skews Their TCRβ Repertoire.
abstract: CD8αα TCRαβ+intestinal intraepithelial lymphocytes play a critical role in promoting intestinal homeostasis, although mechanisms controlling their development and peripheral homeostasis remain unclear. In this study, we examined the spatiotemporal role of Bim in the thymic selection of CD8αα precursors and the fate of these cells in the periphery. We found that T cell-specific expression of Bim during early/cortical, but not late/medullary, thymic development controls the agonist selection of CD8αα precursors and limits their private TCRβ repertoire. During this process, agonist-selected double-positive cells lose CD4/8 coreceptor expression and masquerade as double-negative (DN) TCRαβhithymocytes. Although these DN thymocytes fail to re-express coreceptors after OP9-DL1 culture, they eventually mature and accumulate in the spleen where TCR and IL-15/STAT5 signaling promotes their conversion to CD8αα cells and their expression of gut-homing receptors. Adoptive transfer of splenic DN cells gives rise to CD8αα cells in the gut, establishing their precursor relationship in vivo. Interestingly, Bim does not restrict the IL-15-driven maturation of CD8αα cells that is critical for intestinal homeostasis. Thus, we found a temporal and tissue-specific role for Bim in limiting thymic agonist selection of CD8αα precursors and their TCRβ repertoire, but not in the maintenance of CD8αα intraepithelial lymphocytes in the intestine.
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.|Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45257.
authors.forename: Kun-Po
authors.identifier: 0000-0002-8872-3814
authors.initials: KP
authors.lastname: Li
authors.affiliation: Institute for Anatomy, University of Lübeck, 23538 Lübeck, Germany; and.
authors.forename: Anke
authors.initials: A
authors.lastname: Fähnrich
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.|Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45257.
authors.forename: Eron
authors.identifier: 0000-0002-7181-7929
authors.initials: E
authors.lastname: Roy
authors.affiliation: Rheumatology Division, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Carla M
authors.initials: CM
authors.lastname: Cuda
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.|Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45257.
authors.forename: H Leighton
authors.identifier: 0000-0001-8162-6758
authors.initials: HL
authors.lastname: Grimes
authors.affiliation: Rheumatology Division, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Harris R
authors.identifier: 0000-0003-4174-608X
authors.initials: HR
authors.lastname: Perlman
authors.affiliation: Institute for Anatomy, University of Lübeck, 23538 Lübeck, Germany; and.
authors.forename: Kathrin
authors.identifier: 0000-0002-8929-4249
authors.initials: K
authors.lastname: Kalies
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; David.Hildeman@cchmc.org.|Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45257.
authors.forename: David A
authors.identifier: 0000-0002-0421-8483
authors.initials: DA
authors.lastname: Hildeman
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000072224:Bcl-2-Like Protein 11 / Q000096:biosynthesis* / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D005434:Flow Cytometry; D007422:Intestines / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D060168:Thymocytes / Q000166:cytology* / Q000276:immunology
chemical_list: D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta