SRP126124 PRJNA421032 ?d T cells clonally expand for long-term immunity 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. Herein, a mouse model of S. aureus skin reinfection was developed to investigate protective memory responses. In contrast to wildtype mice, IL-1ß-deficient mice exhibited poor neutrophil recruitment and bacterial clearance during primary infection that was unexpectedly rescued during secondary S. aureus challenge. The rescued response was mediated by ?d T cells from skin-draining lymph nodes that trafficked and produced TNF/IFN? to restore neutrophil recruitment and promote bacterial clearance. This process required compensatory T cell-intrinsic TLR2/MyD88-signaling. RNA-Seq of the lymph nodes revealed a clonotypic S. aureus-induced ?d T cell expansion with a complementarity-determining region 3 (CDR3) amino acid (a.a.) sequence identical to invariant V?5+ dendritic epidermal T cells (DETCs). Unexpectedly, this TRG a.a. sequence of the dominant CDR3 sequence was generated from multiple gene rearrangements of TRGV5 and TRGV6, indicating clonotypic expansion. TNF/IFN?-producing ?d T cells were also expanded in peripheral blood of IRAK4-deficient humans when they were no longer predisposed to S. aureus skin infections. Thus, clonally expanded ?d T cells represent a previously undescribed mechanism for long-lasting immunity against recurrent S. aureus skin infections. Mus musculus