A protective role of CD4⁺ T cells during Staphylococcus aureus craniotomy infection

Craniotomy is a neurosurgery performed to resolve severe neurological complications. Despite prophylaxis, nearly 1-3% of craniotomies are complicated by infection, with approximately half attributed to Staphylococcus aureus (S. aureus). Using our novel mouse model, we established a protective role for CD4⁺ T cells during S. aureus craniotomy infection. Rag1 knock out (KO) mice or animals treated with anti-CD4 Ab showed significantly elevated bacterial burden, suggesting an important role for adaptive immunity in controlling infection. These findings were corroborated in mice treated with VLA-4 and LFA-1 Abs, underscoring the importance of peripheral CD4⁺ T cell responses. scRNA-seq revealed phenotypic heterogeneity within brain CD3⁺ infiltrates with CD4⁺ cells being most predominant that were typified by robust inflammatory and glycolytic profiles. CD4⁺ T cells displayed attributes of both Th1 and Th17 phenotypes, whose functional importance was validated in vivo as adoptive transfer of either Th1 or Th17 cells prevented S. aureus outgrowth in Rag1 KO mice. Interestingly, milder phenotypes were observed in IL-17A/F or IFN-γ KO mice, suggesting a redundant and cooperative role of both Th1 and Th17 driven responses. This was confirmed by treatment of IFN-γ KO mice with IL-17A/F neutralizing Ab, which recapitulated phenotypes of Rag1 KO animals. Collectively, our results implicate a critical role for CD4⁺ T cells in S. aureus containment during craniotomy infection.