Nasal CD4? tissue-resident memory T cells provide cross-protective immunity to influenza

CD4 tissue-resident memory T cells (TRM) 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 after infection and provide protection upon heterosubtypic challenge. 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 promotes CD4 TRM residency in the NT. Furthermore, we show that the NT of mice and humans contains a high frequency of Th17 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 local protection during heterosubtypic IAV infection. Overall design: Here we have infected mice with IAV-PR8 and sacrificed them at 30 days after infection. For each experiment we collected nasal tissue and lungs and either sorted total CD4 TRM (CD4+CD44+CD62L-CD69+) or HA+CD4TRM or NP+CD4TRM cells. Sorted total CD4 TRM from naive mice used as controls. cells from several mice were pooled. Within each experiment, different groups/organs were hashtagged in order to pool more samples together