A Distinct Lung-Interstitium-Resident Memory CD8⁺ T Cell Subset Confers Enhanced Protection to Lower Respiratory Tract Infection

The nature and anatomic location of the protective memory CD8⁺ T cell subset induced by intranasal vaccination remain poorly understood. We developed a vaccination model to assess the anatomic location of protective memory CD8⁺ T cells and their role in lower airway infections. Memory CD8⁺ T cells elicited by local intranasal, but not systemic, vaccination with an engineered non-replicative CD8⁺ T cell-targeted antigen confer enhanced protection to a lethal respiratory viral challenge. This protection depends on a distinct CXCR3^LO resident memory CD8⁺ T (TRM) cell population that preferentially localizes to the pulmonary interstitium. Because they are positioned close to the mucosa, where infection occurs, interstitial TRM cells act before inflammation can recruit circulating memory CD8⁺ T cells into the lung tissue. This results in a local protective immune response as early as 1 day post-infection. Hence, vaccine strategies that induce lung interstitial TRM cells may confer better protection against respiratory pathogens.