The top downregulated pathways in CD28−/− CTLA4−/− mice were regulation of defense response (GO:0031347), regulation of immune effector process (GO:0002697), cytokine signaling (R-MMU-1280215), and herpes simplex infection (Ko05168) pathways (Fig. 6A, CD28−/− CTLA4−/−, downregulated), while the positive regulation of the kinase autophosphorylation pathway (GO:0031954) was upregulated (Fig. 6A, CD28−/− CTLA4−/−, upregulated). The gene discussed is CTLA4; the disease is herpes simplex infectious disease.