Association of cervical cancer with the presence of CD4⁺ regulatory T cells specific for human papillomavirus antigens

Because of their important role in the maintenance of self-tolerance, CD4⁺ regulatory T cells prevent autoimmune diseases but also curtail the efficacy of T cell immune responses against cancers. We now show that this suppressive action of CD4⁺ regulatory T cells is not limited to cancers displaying tumor-associated self antigens, such as melanomas, but also extends to human papillomavirus (HPV)-positive cervical cancers that express foreign tumor antigens. HPV-specific CD4⁺ T cells isolated from lymph node biopsies of cervical cancer patients were found to suppress proliferation and cytokine (IFN-γ, IL-2) production by responder T cells. The capacity of HPV-specific CD4⁺ T cells to exert this suppressive effect depended on their activation by cognate HPV antigen and on close-range interactions with responder T cells. HPV-specific CD4⁺ regulatory T cells were also retrieved from cervical cancer biopsies, suggesting that they interfere with the anti-tumor immune response at both the induction and effector levels. Our findings offer a plausible explanation for the observed failure of the tumor-specific immune response in patients with cervical carcinoma.