CD4+ T cell-innate immune crosstalk is critical during Staphylococcus aureus biofilm infection [RAG KO scRNA-seq]

Access to the brain for treating neurological sequalae requires a craniotomy, which can be complicated by infection. T cells preferentially home to the brain, but not other tissue sites, during Staphylococcus aureus (S. aureus) craniotomy infection; however, their functional importance is unknown. CD4+ T cells were critical for bacterial containment during craniotomy infection as Rag1-/- mice and WT animals treated with anti-CD4 or VLA-4 and LFA-1 antibodies exhibited elevated bacterial burdens. scRNA-seq revealed transcriptional heterogeneity in brain CD3+ infiltrates, with CD4+ cells most prominent and typified by both Th1 and Th17 signatures, and adoptive transfer of either subset in Rag1-/- mice prevented S. aureus outgrowth. scRNA-seq revealed a profound IFN-γ signature in innate immune cells from Rag1-/- mice during craniotomy infection, supporting extensive T cell-innate immune crosstalk that was validated by immunostaining in the brain parenchyma. A cooperative role for Th1 and Th17 driven responses was demonstrated by treatment of Ifng-/- mice with IL-17A/F neutralizing Ab that recapitulated phenotypes observed in Rag1-/- animals, which were not observed following the loss of either cytokine alone. Collectively, these results implicate a critical role for CD4+ T cells in S. aureus containment during craniotomy infection by shaping the innate immune landscape.