Naive T cell activation in the draining lymph nodes is accelerated by airway resident CD4 T cell activation

Abstract Tissue-resident memory CD4 T cells (TRM) protect against pathogens through the early shaping of inflammation at sites of infection. The extent to which their activation can impact subsequent systemic T cell responses is not clear. To ask if lung CD4 TRM recognizing antigen can impact systemic T cell responses against the same antigen presented in secondary lymphoid organs, we generated OVA-specific lung TRM primed by infection with an influenza virus expressing OVA peptide. We isolated the OVA-specific TRM 30 days after infection and transferred one million to naive mice intranasally resulting in an airway-resident TRM cohort similar in magnitude to TRM generated in virus-primed mice. We then recalled the transferred TRM by intranasal administration of FITC-labelled OVA protein to focus on TRM recall in the absence of virus-induced inflammation. One day after OVA challenge more FITC+ APC were present in the draining lymph nodes (dLN) of mice with TRM, suggesting antigen presentation to systemic T cells may be accelerated in the presence of airway TRM. We confirmed this by tracking naive OVA-specific CD4 T cells (OT-II) and CD8 T cell (OT-I) cohorts transferred i.v. to mice harboring OVA-specific TRM or not: more responding naive cells, expressing higher levels of activation markers, were detected 3 days after OVA challenge in mice with TRM. By 4 days, more responding cells were present in the lungs of TRM recipients, indicating that TRM and systemic T cell responses form a circuit via enhanced antigen presentation in the lymph nodes. Our results suggest that enhanced kinetics of systemic T cell activation induced by TRM activation in the airways may represent a novel mechanism of their protection against influenza and other respiratory viruses.