Adenovirus Serotype 5 Vectors Trigger IL-27-Dependent Inhibitory CD4⁺ T Cell Responses

Abstract

Viral vectors are attractive vaccine platforms that elicit robust innate and adaptive immune responses, but they vary greatly in their ability to induce protective immunity. Adenovirus serotype 5 (Ad5) vectors elicit robust CD8⁺ T cell responses but are typically characterized by an exhausted phenotype. The mechanisms by which Ad5 vectors induce dysfunctional CD8⁺ T cells have not been fully elucidated. Here we demonstrate that Ad5 vectors, but not Ad26 vectors, elicit exhausted antigen-specific IL-10⁺PD1⁺ CD4⁺ T cells with a dysfunctional transcriptional profile, and these cells effectively suppress CD8⁺ T cell responses in vivo. The blockade of IL-10 increased the frequency of antigen-specific CD8⁺ T cells with enhanced cytokine polyfunctionality and protective capacity against a Listeria monocytogenes challenge. Induction of inhibitory CD4⁺ T cells by Ad5 vectors is associated with increased IL-27 expression, and IL-27 blockade improves CD4⁺ T cell cytokine polyfunctionality. Together our data highlight a novel role for IL-27 induced inhibitory CD4⁺ T cells in regulating responses to viral vector vaccines.