CD4⁺ T cell–innate immune crosstalk is critical during Staphylococcus aureus craniotomy infection

Access to the brain for treating neurological sequalae requires a craniotomy, which can be complicated by infection. Staphylococcus aureus accounts for half of craniotomy infections, increasing morbidity in a medically fragile patient population. T cells preferentially traffic to the brain during craniotomy infection; however, their functional importance is unknown. Using a mouse model of S. aureus craniotomy infection, CD4⁺ T cells were critical for bacterial containment, as treatment of WT animals with anti-CD4 exacerbated infection that was similar to phenotypes in Rag1^–/– mice. Single-cell RNA-Seq (scRNA-Seq) revealed transcriptional heterogeneity in brain CD3⁺ infiltrates, with CD4⁺ cells most prominent that displayed Th1- and Th17-like characteristics, and adoptive transfer of either subset in Rag1^–/– animals during early infection prevented S. aureus outgrowth. scRNA-Seq identified a robust IFN signature in several innate immune clusters, and examination of cell-to-cell interactions revealed extensive T cell crosstalk with monocytes/ macrophages that was also observed in human craniotomy infection. A cooperative role for Th1 and Th17 responses was demonstrated by treatment of Ifng^–/– mice with IL-17A neutralizing antibody that recapitulated phenotypes in Rag1^–/– animals. Collectively, these findings implicate Th1- and Th17-mediated proinflammatory responses in shaping the innate immune landscape for S. aureus containment during craniotomy infection.