Nasal tissue-resident memory CD4+T cells persist after influenza A virus infection and provide heterosubtypic protection

Abstract CD4 tissue-resident memory T (CD4 TRM) cells are crucial adaptive immune components involved in preventing influenza A virus (IAV) infection. Despite their importance, their physiological role in the upper respiratory tract, the first site of contact with IAV, remains unclear. Here, we find that, after IAV infection, antigen-specific CD4 TRM persist in the nasal tissue (NT) compartment and play a prime role in local viral clearance. Single cell RNA sequencing analysis reveals that NT CD4 TRM are heterogeneous and transcriptionally distinct as compared to their lung counterparts. Mechanistically, we demonstrate that the CXCR6- CXCL16 axis is involved in CD4 TRM residency in the NT. Furthermore, we show that the NT of mice and humans contains a high frequency of IL-17-producing CD4 TRM that aid in local viral clearance and in reducing tissue damage. Collectively, our results support a robust physiological role for nasal tissue CD4 TRM in preventing IAV infection.