As CD4+ T cells enhanced neoplastic progression in HPV16‐induced skin cancer (Daniel et al, 2003) and promoted skin tumorigenesis in DMBA/TPA‐ and UV‐induced skin cancer models (Yusuf et al, 2008; Nasti et al, 2011), and because of the increase in CD4‐positive Tregs, we intercrossed Act and HPV8 with CD4‐deficient mice and analyzed spontaneous tumorigenesis in the single, double, and triple mutant progeny. The gene discussed is CD4; the disease is skin neoplasm.