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

Abstract

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 T_RM 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.