Pathobiont-induced suppressive immune imprints thwart T cell vaccine responses

Pathobionts have evolved many strategies to coexist with the host, but how immune evasion mechanisms contribute to the difficulty of developing vaccines against pathobionts is unclear. Meanwhile, Staphylococcus aureus (SA) has resisted human vaccine development to date. Here we show that prior SA exposure induces non-protective CD4⁺ T cell imprints, leading to the blunting of protective IsdB vaccine responses. Mechanistically, these SA-experienced CD4⁺ T cells express IL-10, which is further amplified by vaccination and impedes vaccine protection by binding with IL-10Rα on CD4⁺ T cell and inhibit IL-17A production. IL-10 also mediates cross-suppression of IsdB and sdrE multi-antigen vaccine. By contrast, the inefficiency of SA IsdB, IsdA and MntC vaccines can be overcome by co-treatment with adjuvants that promote IL-17A and IFN-γ responses. We thus propose that IL-10 secreting, SA-experienced CD4⁺ T cell imprints represent a staphylococcal immune escaping mechanism that needs to be taken into consideration for future vaccine development.