CTLA4 and autoimmune disease: Finally, accumulating genetic data in mice suggest that the original concept35,36 that CTLA-4 negatively regulates T cell activation and that such regulation is achieved through Shp-241,42 may need to be revisited.43 Thus, while the severe autoimmune diseases in Ctla4−/− mice have been used to support the notion of CTLA-4 as a cell-intrinsic negative regulator for T cell activation,44,45 at least three lines of genetic data have since emerged that are not consistent with this view.