Blocking inducible co‐stimulator in the absence of CD28 impairs Th1 and CD25+ regulatory T cells in murine colitis

Several autoimmune disease models depend on an imbalance in the activation of aggressor Th1 and CD4+CD25+ regulatory T (Treg) cells. Here we compare the requirement for signals through the co‐stimulatory molecules CD28 and inducible co‐stimulator (ICOS) in chronic murine colitis, a model for inflammatory bowel disease. We used a colitis model in which disease‐causing CD45RBhi T cells alone or in combination with CD4+CD25+ T cells from either CD28‐deficient or wild‐type donors were transferred into T cell‐deficient animals, half of which were treated with ICOS‐blocking reagents. Blocking ICOS on the surface of CD28‐deficient Th1 cells abrogated development of colitis, whereas blocking CD28 or ICOS alone had little to no effect on disease induction. In contrast to Th1 cells, regulatory T cell functioning depended mostly on CD28 signaling with only a minor contribution for ICOS. We conclude that CD28 and ICOS collaborate to development of murine colitis by aggressor Th1 cells, and that CD28 is required for Treg cells, which should caution against the use of CD28‐blocking reagents in inflammatory bowel disease.