γδ T cells clonally expand for long-term immunity against Staphylococcus aureus skin reinfection. Mus musculus

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-1β-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 γδ T cells from skin-draining lymph nodes that trafficked and produced TNF/IFNγ 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 γδ T cell expansion with a complementarity-determining region 3 (CDR3) amino acid (a.a.) sequence identical to invariant Vγ5+ 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/IFNγ-producing γδ 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 γδ T cells represent a previously undescribed mechanism for long-lasting immunity against recurrent S. aureus skin infections.