Abstract
Tissue-resident memory (TRM) CD8+ T cells are positioned within environmental barrier tissues to provide a first line of defense against pathogen entry, but whether these specialized T cell populations can be readily boosted to increase protective immunity is ill defined. Here, we demonstrate that repeated activation of rare, endogenous TRM CD8+ T cells, using only topical application of antigenic peptide causes delayed-type hypersensitivity and increases the number of antigen-specific TRM CD8+ T cells, specifically in the challenged skin by ∼15-fold. Expanded TRM CD8+ T cells in the skin are derived from memory T cells recruited out of the circulation that became CD69+ tissue residents following a local antigen encounter. Notably, recruited circulating memory CD8+ T cells of a different antigen specificity could be coerced to become tissue resident using a dual-peptide challenge strategy. Expanded TRM CD8+ T cells significantly increase anti-viral protection, suggesting that this approach could be used to rapidly boost tissue-specific cellular immunity.