title: The transcription factor T-bet is induced by IL-15 and thymic agonist selection and controls CD8αα(+) intraepithelial lymphocyte development.
abstract: CD8αα(+) intraepithelial lymphocytes (IELs) are instrumental in maintaining the epithelial barrier in the intestine. Similar to natural killer cells and other innate lymphoid cells, CD8αα(+) IELs constitutively express the T-box transcription factor T-bet. However, the precise role of T-bet for the differentiation or function of IELs is unknown. Here we show that mice genetically deficient for T-bet lacked both TCRαβ(+) and TCRγδ(+) CD8αα(+) IELs and thus are more susceptible to chemically induced colitis. Although T-bet was induced in thymic IEL precursors (IELPs) as a result of agonist selection and interleukin-15 (IL-15) receptor signaling, it was dispensable for the generation of IELPs. Subsequently, T-bet was required for the IL-15-dependent activation, differentiation, and expansion of IELPs in the periphery. Our study reveals a function of T-bet as a central transcriptional regulator linking agonist selection and IL-15 signaling with the emergence of CD8αα(+) IELs.
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Freiburg Medical Center, 79104 Freiburg, Germany; Department of Internal Medicine IV, University of Freiburg Medical Center, 79106 Freiburg, Germany.
authors.forename: Christoph S N
authors.initials: CS
authors.lastname: Klose
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Freiburg Medical Center, 79104 Freiburg, Germany; Department of Internal Medicine IV, University of Freiburg Medical Center, 79106 Freiburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Blatz
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Freiburg Medical Center, 79104 Freiburg, Germany; Department of Internal Medicine IV, University of Freiburg Medical Center, 79106 Freiburg, Germany.
authors.forename: Yannick
authors.initials: Y
authors.lastname: d'Hargues
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Freiburg Medical Center, 79104 Freiburg, Germany; Institute of Medical Microbiology and Hygiene, University of Mainz Medical Center, 55131 Mainz, Germany.
authors.forename: Pedro P
authors.initials: PP
authors.lastname: Hernandez
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Freiburg Medical Center, 79104 Freiburg, Germany; Institute of Medical Microbiology and Hygiene, University of Mainz Medical Center, 55131 Mainz, Germany; International Max Planck Research School for Molecular and Cellular Biology, 79108 Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kofoed-Nielsen
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Freiburg Medical Center, 79104 Freiburg, Germany; Department of Internal Medicine IV, University of Freiburg Medical Center, 79106 Freiburg, Germany.
authors.forename: Juliane F
authors.initials: JF
authors.lastname: Ripka
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Freiburg Medical Center, 79104 Freiburg, Germany; Department of Internal Medicine IV, University of Freiburg Medical Center, 79106 Freiburg, Germany; Faculty of Biology, 79104 Freiburg, Germany.
authors.forename: Karolina
authors.initials: K
authors.lastname: Ebert
authors.affiliation: Department of Internal Medicine IV, University of Freiburg Medical Center, 79106 Freiburg, Germany; BIOSS Center of Biological Signalling Studies, 79104 Freiburg, Germany.
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Arnold
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Mainz Medical Center, 55131 Mainz, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Diefenbach
authors.affiliation: Laboratory of Transplantation Immunology, Departments of Biomedicine and Nephrology, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Ed
authors.initials: E
authors.lastname: Palmer
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Freiburg Medical Center, 79104 Freiburg, Germany; Department of Internal Medicine IV, University of Freiburg Medical Center, 79106 Freiburg, Germany. Electronic address: yakup.tanriver@uniklinik-freiburg.de.
authors.forename: Yakup
authors.initials: Y
authors.lastname: Tanriver
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016827:CD8 Antigens / Q000096:biosynthesis*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D003092:Colitis / Q000139:chemically induced / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology; D019409:Interleukin-15 / Q000235:genetics* / Q000276:immunology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology; D007422:Intestines / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics*; D053647:Receptors, Interleukin-15 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics*; D000098815:T-bet Transcription Factor
chemical_list: D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D019409:Interleukin-15; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D053647:Receptors, Interleukin-15; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor