PSMε controls skin commensal CD8 ⁺ T cell activation

Upon skin colonization, the prevalent human skin commensal S. epidermidis can elicit a CD8 ⁺ T cell response that protects against pathogens or clears tumors. The microbial features that drive this response are undefined, limiting our ability to understand and predict commensal-immune crosstalk and to engineer potent commensal-derived immunotherapies. To uncover these microbial features, we harnessed both the natural variation in CD8 ⁺ T cell induction across primary human isolates of Staphylococcus and our ability to genetically manipulate these strains. Stimulatory strains exhibit increased quorum sensing activation, which turns on a unique commensal-associated gene family, called phenol-soluble modulin ε (PSMε), that is required for CD8 ⁺ T cell activation. PSMε not only acts as the immunodominant CD8 ⁺ T cell antigen but also enhances cross-presentation in an antigen-agnostic manner. Co-delivering PSMε promotes CD8 ⁺ T cell priming to an exogenous antigen via a mechanism that is independent of formyl peptide receptor and co-stimulatory receptor upregulation. Thus, we demonstrate that specific aspects of microbiome-immune crosstalk can be distilled to molecular components, which engage in previously undescribed mechanisms and can be harnessed for immunotherapy without requiring live bacterial colonization.