The ARNT–STAT3 axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+ cells

• Published in: Nature communications 2013-07, Vol.4 (1), p.2112-2112, Article 2112
• Main Authors: Nakajima, Kohei, Maekawa, Yoichi, Kataoka, Keiko, Ishifune, Chieko, Nishida, Jun, Arimochi, Hideki, Kitamura, Akiko, Yoshimoto, Takayuki, Tomita, Shuhei, Nagahiro, Shinji, Yasutomo, Koji
• Format: Article
• Language: English
• Subjects: 631/136/142; 631/250/1619/554; 631/250/347; 631/80/86; Animals; Aryl Hydrocarbon Receptor Nuclear Translocator - deficiency; Aryl Hydrocarbon Receptor Nuclear Translocator - genetics; Aryl Hydrocarbon Receptor Nuclear Translocator - immunology; beta-Naphthoflavone - pharmacology; CD8 Antigens - genetics; CD8 Antigens - immunology; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation; Cells, Cultured; Female; Gene Expression Regulation; Humanities and Social Sciences; Interleukin-15 - pharmacology; Intestinal Mucosa - cytology; Intestinal Mucosa - immunology; Intestines - cytology; Intestines - drug effects; Intestines - immunology; Mice; Mice, Inbred C57BL; Mice, Transgenic; multidisciplinary; Precursor Cells, T-Lymphoid - cytology; Precursor Cells, T-Lymphoid - immunology; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - immunology; Science; Science (multidisciplinary); Signal Transduction; STAT3 Transcription Factor - deficiency; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - immunology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms3112

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. Intraepithelial lymphocytes (IELs) defend against pathogens in the gut, and their differentiation depends on both diet and microbiota-derived factors. Nakajima et al . show that signalling through the aryl hydrocarbon receptor nuclear translocator and STAT3 is required for the development of a subset of IELs.