To test whether activated CD4+ T cells lacking HDAC1 and HDAC2 acquire CD4+ CTL characteristics, including gene signatures and cytolytic activity, and whether CD4+ CTL induction in response to viral infection is regulated by HDAC1 and HDAC2, we generated mice with a T cell–specific combinatorial deletion of 3 of the 4 Hdac1 and Hdac2 alleles. This evidence concerns the gene HDAC2 and viral infectious disease.