Circumvention of regulatory CD4⁺ T cell activity during cross-priming strongly enhances T cell-mediated immunity

Immunization with purified antigens is a safe and practical vaccination strategy but is generally unable to induce sustained CD8⁺ T cell-mediated protection against intracellular pathogens. Most efforts to improve the CD8⁺ T cell immunogenicity of these vaccines have focused on co-administration of adjuvant to support cross-presentation and dendritic cell maturation. In addition, it has been shown that CD4⁺ T cell help during the priming phase contributes to the generation of protective CD8⁺ memory T cells. In this report we demonstrate that the depletion of CD4⁺ T cells paradoxically enhances long-lasting CD8-mediated protective immunity upon protein vaccination. Functional and genetic in vivo inactivation experiments attribute this enhancement primarily to MHC class II-restricted CD4⁺ regulatory T cells (Treg), which appear to physiologically suppress the differentiation process towards long-living effector memory T cells. Since, in functional terms, this suppression by Treg largely exceeds the positive effects of conventional CD4⁺ T cell help, even the absence of all CD4⁺ T cells or lack ofMHCclass II-mediated interactions on priming dendritic cells result in enhanced CD8⁺ T cell immunogenicity. These findings have important implications for the improvement of vaccines against intracellular pathogens or tumors, especially in patients with highly active Treg.