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

Lung-resident memory CD8 T cells (T-RM) 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 T-RM contrasts sharply with long-term maintenance of T-RM induced by localized infections in the skin and in other tissues. We show that the decline in lung T-RM 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 (T-EM) rather than central memory cells (T-cM) are the precursors for conversion to lung T-RM. Time-dependent changes in expression of genes critical for lymphocyte trafficking and T-RM differentiation, in concert with enrichment of T-cm , diminish the capacity of circulating memory CD8 T cells to form T-RM with time, explaining why IAV-induced T-RM are not stably maintained. Systemic booster immunization, through increasing the number of circulating T-EM, increases lung T-RM, providing a potential new avenue to enhance IAV vaccines.