Single-Cell Profiling Identifies Skin-Resident Memory CD4+ T Cells as a Potential Correlate of Immunity During Staphylococcus aureus Skin Infection.

Staphylococcus aureus is a leading cause of skin and soft tissue infections (SSTIs), yet the cellular mediators of protective memory remain incompletely defined. Using a self-resolving murine SSTI model, we combined longitudinal single-cell RNA sequencing with flow cytometry to characterize immune memory within the skin following infection. We identified a persistent population of CD4+ T cells that remained in the skin after bacterial clearance and acquired a transcriptional program consistent with tissue residency, including expression of genes associated with tissue retention and long-term residence. Phenotypic analysis confirmed the emergence of a skin-resident memory T cell (Trm) population that persisted well beyond resolution of infection and displayed characteristics of a clonal T cell response. Upon reinfection, protective immunity was associated with rapid recall responses from these resident cells and was maintained despite FTY720-mediated blockade of lymphocyte egress from secondary lymphoid organs, demonstrating that circulating lymphocytes were dispensable for protection. Together, these findings identify infection-induced CD4+ Trms as a durable component of immune memory following S. aureus SSTI and support a role for tissue-resident immunity in protection against recurrent infection, highlighting CD4+ Trms as a potential target for future vaccine strategies.