Vaccine-generated lung tissue–resident memory T cells provide heterosubtypic protection to influenza infection

TLDR

Tissue‑resident memory T cells (TRM) are a recently defined, noncirculating subset capable of rapid in‑situ protective responses, yet their generation and role in vaccine‑mediated immunity remain unclear. The study aimed to determine whether licensed influenza vaccines could generate lung‑resident memory T cells and provide localized protection. The authors evaluated TRM generation and lung‑localized protection after administering injectable inactivated influenza virus (IIV, Fluzone) and intranasal live‑attenuated influenza virus (LAIV, FluMist) vaccines. LAIV, but not IIV, induced lung CD4⁺ and CD8⁺ TRM that conferred long‑term, cross‑strain protection independent of antibodies, whereas intranasal IIV or injected LAIV failed to elicit TRM or protection, underscoring the need for respiratory delivery of a live‑attenuated strain to establish durable lung immunity.

Abstract

Tissue-resident memory T cells (TRM) are a recently defined, noncirculating subset with the potential for rapid in situ protective responses, although their generation and role in vaccine-mediated immune responses is unclear. Here, we assessed TRM generation and lung-localized protection following administration of currently licensed influenza vaccines, including injectable inactivated influenza virus (IIV, Fluzone) and i.n. administered live-attenuated influenza virus (LAIV, FluMist) vaccines. We found that, while IIV preferentially induced strain-specific neutralizing antibodies, LAIV generated lung-localized, virus-specific T cell responses. Moreover, LAIV but not IIV generated lung CD4+ TRM and virus-specific CD8+ TRM, similar in phenotype to those generated by influenza virus infection. Importantly, these vaccine-generated TRM mediated cross-strain protection, independent of circulating T cells and neutralizing antibodies, which persisted long-term after vaccination. Interestingly, intranasal administration of IIV or injection of LAIV failed to elicit T cell responses or provide protection against viral infection, demonstrating dual requirements for respiratory targeting and a live-attenuated strain to establish TRM. The ability of LAIV to generate lung TRM capable of providing long-term protection against nonvaccine viral strains, as demonstrated here, has important implications for protecting the population against emergent influenza pandemics by direct fortification of lung-specific immunity.