title: The ARNT-STAT3 axis regulates the differentiation of intestinal intraepithelial TCRαβ⁺CD8αα⁺ cells.
abstract: Intestinal intraepithelial T cells contribute to the regulation of inflammatory responses in the intestine; however, the molecular basis for their development and maintenance is unknown. The aryl hydrocarbon receptor complexes with the aryl hydrocarbon receptor nuclear translocator (ARNT) and senses environmental factors, including gut microbiota. Here, we identify ARNT as a critical regulator of the differentiation of TCRαβ(+)CD8αα(+) intestinal intraepithelial T cells. Mice deficient in either ARNT or aryl hydrocarbon receptor show a greater than- eight-fold reduction in the number of TCRαβ(+)CD8αα(+) intestinal intraepithelial T cells. The number of TCRαβ(+)CD8αα(+) intestinal intraepithelial T cells is increased by treatment with an aryl hydrocarbon receptor agonist in germ-free mice and is decreased by antibiotic treatment. The Arnt-deficient precursors of TCRαβ(+)CD8αα(+) intestinal intraepithelial T cells express low amounts of STAT3 and fail to differentiate towards the TCRαβ(+)CD8αα(+) cell fate after IL-15 stimulation, a deficiency that is overcome by overexpression of Stat3. These data demonstrate that the ARNT-STAT3 axis is a critical regulator of TCRαβ(+)CD8αα(+) intestinal intraepithelial T-cell development and differentiation.
authors.affiliation: Department of Immunology & Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Nakajima
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Maekawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Kataoka
authors.forename: Chieko
authors.initials: C
authors.lastname: Ishifune
authors.forename: Jun
authors.initials: J
authors.lastname: Nishida
authors.forename: Hideki
authors.initials: H
authors.lastname: Arimochi
authors.forename: Akiko
authors.initials: A
authors.lastname: Kitamura
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshimoto
authors.forename: Shuhei
authors.initials: S
authors.lastname: Tomita
authors.forename: Shinji
authors.initials: S
authors.lastname: Nagahiro
authors.forename: Koji
authors.initials: K
authors.lastname: Yasutomo
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D019409:Interleukin-15 / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000166:cytology* / Q000276:immunology; D007422:Intestines / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology* / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D019324:beta-Naphthoflavone / Q000494:pharmacology
chemical_list: C497397:Arnt protein, mouse; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D019409:Interleukin-15; D016693:Receptors, Antigen, T-Cell, alpha-beta; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D019324:beta-Naphthoflavone