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 CXCR3LO 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. [Display omitted] •Intranasal T cell epitope-targeted vaccination confers enhanced protection•Intranasal vaccination preferentially induces CXCR3LO lung-resident memory CD8+ T cells•Protective memory T cells localize to vulnerable sites of the lung interstitium•Interstitial memory CD8+ T cells rapidly protect the lung against infection Mucosal surveillance ensures rapid protection when a pathogen breaches the barrier. Gilchuk et al. report that local vaccination elicits a distinct resident memory CD8+ T cell subset that localizes to the lung interstitium. These T cells protect against respiratory infections by positioning at vulnerable sites and acting quickly against infections.