In relation to our findings on the compensation for the absence of ICOS via the upregulation of CD28 expression in the cytotoxic activity of CD8+ T cells in their recall responses to T. gondii antigens, a previous study with infections with lymphocytic choriomeningitis virus and vesicular stomatitis virus demonstrated that the blocking of ICOS signaling by ICOS-Ig markedly impaired IFN-γ production of CD4+ T cells against the viruses in CD28−/− mice, whereas ICOS-Ig treatment in WT mice had only a limited downregulatory effect on IFN-γ production [26]. This evidence concerns the gene CD4 and infection.