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

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 TCR alpha beta(+) CD8 alpha alpha(+) intestinal intraepithelial T cells. Mice deficient in either ARNT or aryl hydrocarbon receptor show a greater than- eight-fold reduction in the number of TCR alpha beta(+) CD8 alpha alpha(+) intestinal intraepithelial T cells. The number of TCR alpha beta(+) CD8 alpha alpha(+) 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 TCR alpha beta(+) CD8 alpha alpha(+) intestinal intraepithelial T cells express low amounts of STAT3 and fail to differentiate towards the TCR alpha beta(+) CD8 alpha alpha(+) 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 TCR alpha beta(+) CD8 alpha alpha(+) intestinal intraepithelial T-cell development and differentiation.