ICOS-deficient regulatory T cells display normal induction of Il10 but readily downregulate expression of Foxp3

The ICOS pathway has been implicated in the development and functions of regulatory T cells (Treg cells) including those producing IL-10. Treg cell-derived IL-10 is indispensable for the establishment and maintenance of intestinal immune homeostasis. We examined the possible involvement of the ICOS pathway in the accumulation of murine colonic Foxp3- and/or IL-10-expressing cells. We show that, ICOS deficiency does not impair induction of IL-10 by intestinal CD4 T cells, but instead triggers substantial reductions in gut-resident and peripherally-derived Foxp3 + Treg cells. ICOS deficiency is associated with reduced demethylation of Foxp3 CNS2 and enhanced loss of Foxp3. This instability significantly limits the ability of ICOS-deficient Treg cells to reverse ongoing inflammation. Collectively, our results identify a novel role for ICOS co-stimulation in imprinting the functional stability of Foxp3 that is required for the retention of full Treg cell function in the periphery.