Establishment and Maintenance of Conventional and Circulation-Driven Lung-Resident Memory CD8(+) T Cells Following Respiratory Virus Infections

Antigen-specific CD8(+) tissue-resident memory T cells (T(RM) cells) persist in the lung following resolution of a respiratory virus infection and provide first-line defense against reinfection. In contrast to other memory T cell populations, such as central memory T cells that circulate between lymph and blood, and effector memory T cells (T(EM) cells) that circulate between blood and peripheral tissues, T(RM) cells are best defined by their permanent residency in the tissues and their independence from circulatory T cell populations. Consistent with this, we recently demonstrated that CD8(+) T(RM) cells primarily reside within specific niches in the lung (Repair-Associated Memory Depots; RAMD) that normally exclude CD8(+) T(EM) cells. However, it has also been reported that circulating CD8(+) T(EM) cells continuously convert into CD8(+) T(RM) cells in the lung interstitium, helping to sustain T(RM) numbers. The relative contributions of these two mechanisms of CD8(+) T(RM) cells maintenance in the lung has been the source of vigorous debate. Here we propose a model in which the majority of CD8(+) T(RM) cells are maintained within RAMD (conventional T(RM)) whereas a small fraction of T(RM) are derived from circulating CD8(+) T(EM) cells and maintained in the interstitium. The numbers of both types of T(RM) cells wane over time due to declines in both RAMD availability and the overall number of T(EM) in the circulation. This model is consistent with most published reports and has important implications for the development of vaccines designed to elicit protective T cell memory in the lung.