Clonally Expanded Gamma Delta T Cells Protect Against Staphylococcus Aureus Skin Reinfection

The mechanisms that mediate durable protection against Staphylococcus aureus skin reinfections are unclear, as recurrences are common despite high antibody titers and memory T cells. Here, we developed a mouse model of S. aureus skin reinfection to investigate protective memory responses. In contrast with WT mice, IL-1 beta-deficient mice exhibited poor neutrophil recruitment and bacterial clearance during primary infection that was rescued during secondary S. aureus challenge. The gamma delta T cells from skin-draining LNs utilized compensatory T cell-intrinsic TLR2/MyD88 signaling to mediate rescue by trafficking and producing TNF and IFN-gamma, which restored neutrophil recruitment and promoted bacterial clearance. RNA-sequencing (RNA-seq) of the LNs revealed a clonotypic S. aureus-induced yo T cell expansion with a complementarity-determining region 3 (CDR3) aa sequence identical to that of invariant V gamma 5* dendritic epidermal T cells. However, this T cell receptor gamma (TRG) aa sequence of the dominant CDR3 sequence was generated from multiple gene rearrangements of TRGVS and TRGV6, indicating clonotypic expansion. TNF- and IFN-gamma-producing gamma delta T cells were also expanded in peripheral blood of IRAK4-deficient humans no longer predisposed to S. aureus skin infections. Thus, clonally expanded gamma delta T cells represent a mechanism for long-lasting immunity against recurrent S. aureus skin infections.