Staphylococcus aureus-specific TIGIT+ Treg are present in the blood of healthy subjects – a hurdle for vaccination?

<i>Staphylococcus aureus</i> poses an enormous burden of morbidity and mortality worldwide. Making an efficacious vaccine has however proven extremely challenging. Due to colonizing interactions, pre-existing <i>S. aureus</i>-specific CD4⁺ T cells are often found in the human population and yet a detailed characterization of their phenotypes and how they might in turn impact vaccine efficacy are thus far unknown. Using an activation induced marker assay to sort for <i>S. aureus</i>-specific CD4⁺ T cells in an effector function-independent manner, single cell transcriptomic analysis was conducted. Remarkably, <i>S. aureus</i>-specific CD4⁺ T cells consisted not only of a broader spectrum of conventional T cells (Tcon) than previously described but also of regulatory T cells (Treg). As compared to polyclonally-activated CD4⁺ T cells, <i>S. aureus</i>-specific Tcon were enriched for the expression of the Th17-type cytokine genes <i>IL17A</i>, <i>IL22</i> and <i>IL26</i>, while higher percentages of <i>S. aureus</i>-specific Treg expressed the T Cell Immunoreceptor with Ig and ITIM domains (TIGIT), a pleiotropic immune checkpoint. Notably, the antagonistic anti-TIGIT mAb Tiragolumab increased IL-1β production in response to <i>S. aureus in vitro</i>. Therefore, these results uncover the presence of <i>S. aureus</i>-specific TIGIT⁺ Treg in the blood of healthy subjects that could blunt responses to vaccination and indicate TIGIT as a potential targetable biomarker to overcome pre-exposure-induced immunosuppression.