GITR on the surface of antigen presenting cells, but not on T cells, regulates the pathogenesis of CD4+ T cell-mediated experimental colitis

The receptor GITR is thought to function on the surface of regulatory and activated effector CD4+ T cells. To better understand the role of GITR in in vivo immune responses, we use an established experimental colitis model. Chronic enterocolitis was induced by the transfer of wt or GITR−/− CD4+ T cells into either GITR−/− x Rag−/− or Rag−/− recipients. When non-fractionated CD4+ cells from either wt or GITR−/− donors were transferred, colitis unexpectedly developed in GITR−/− x Rag−/−, but not in Rag−/− recipients. In these mice, the percentage of Treg and Th17 cells is decreased, whilst that of Th1 cells increased. Furthermore, Tregs fail to prevent colitis in GITR−/− x Rag−/− recipients. This is not due to an aberrant function of GITR−/− Treg or Teff cells, but is caused by an imbalance in the number of tolerogenic CD103+ and PDCA1+ plasmacytoid dendritic cells in the GITR−/− mouse. This in turn impairs Treg development and expands the Th1 population in GITR−/− x Rag−/− recipients upon the transfer of non-fractionated CD4+ cells. We conclude that for the induction of colitis, GITR is dispensable on the surface of Treg and Teff cells, nor do GITR-L / GITR interactions on T cells play a role in controlling the disease. GITR, however, controls in vivo DC and monocyte development and in its absence aggravated chronic enterocolitis is caused by an imbalance of colitogenic Th1 cells and regulatory T cells.