Dynamics of influenza-induced lung-resident memory T cells underlie waning heterosubtypic immunity.

Lung-resident memory CD8 T cells (TRM) induced by influenza A virus (IAV) that are pivotal for providing subtype-transcending protection against IAV infection (heterosubtypic immunity) are not maintained long term, causing gradual loss of protection. The short-lived nature of lung TRM contrasts sharply with long-term maintenance of TRM induced by localized infections in the skin and in other tissues. We show that the decline in lung TRM is determined by an imbalance between apoptosis and lung recruitment and conversion to TRM of circulating memory cells. We show that circulating effector memory cells (TEM) rather than central memory cells (TCM) are the precursors for conversion to lung TRM Time-dependent changes in expression of genes critical for lymphocyte trafficking and TRM differentiation, in concert with enrichment of TCM, diminish the capacity of circulating memory CD8 T cells to form TRM with time, explaining why IAV-induced TRM are not stably maintained. Systemic booster immunization, through increasing the number of circulating TEM, increases lung TRM, providing a potential new avenue to enhance IAV vaccines.