CTLA4 and viral infectious disease: The lack of a cell-intrinsic negative regulator effect is also demonstrated by the fact that in the chimeric mice, no preferential expansion of Ctla4−/− T cells was observed during viral infection.48 Third, T cell-specific deletion of Shp2, which was proposed to mediate negative regulation of CTLA-4,41,42 turned out to reduce rather than enhance T cell activation.49 In the context of these genetic data reported since CTLA-4 was proposed as negative regulator for T cell activation, our present data call for a reappraisal of the CTLA-4 checkpoint blockade hypothesis in cancer immunotherapy.