A NOVEL POPULATION OF CD8 MEMORY T CELLS PROTECTS LUNG AFTER SKIN VACCINATION

Respiratory viral pathogens have caused some of the most significant pandemics in modern history, such as the 1918 influenza A, SARS-CoV, and SARS-CoV-2. Although each of these viruses poses distinct challenges, they all share a common route of infection via the respiratory system. Currently, our capability to develop safe and effective vaccines for these viruses is still lacking. In this study, we demonstrate that vaccination with modified vaccinia virus (MVA) through epidermal disruption (e.d.) is significantly more effective than subcutaneous (s.c.), intradermal (i.d.), or intramuscular (i.m.) administration in protecting mice from a lethal influenza challenge. We observed that e.d. vaccination induces a lung-specific tropism in CD8+ T cells, which are long-lasting and predominantly located in the lung vasculature. Longitudinal analysis showed that T cells quickly migrate into the lung tissue within hours after influenza exposure. Remarkably, this T cell influx within 72 hours was sufficient for protection, without the need for priming and expansion in the bronchopulmonary lymph nodes. Single-cell RNA sequencing (scRNASeq) revealed that lung intravascular T cells represent a distinct population from effector and central memory T cells found in the blood, spleen, and lymph nodes. Overall, our findings identify a unique subset of CD8 memory T cells generated through skin immunization, which preferentially localize in the lung intravascular space and offer potent immune protection.