Blocking inducible co-stimulator in the absence of CD28 impairs T_h1 and CD25+ regulatory T cells in murine colitis

Several autoimmune disease models depend on an imbalance in the activation of aggressor T_h1 and CD4⁺CD25⁺ regulatory T (T_reg) 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 CD45RB^hi 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 T_h1 cells abrogated development of colitis, whereas blocking CD28 or ICOS alone had little to no effect on disease induction. In contrast to T_h1 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 T_h1 cells, and that CD28 is required for T_reg cells, which should caution against the use of CD28-blocking reagents in inflammatory bowel disease.