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.