Interstitial-resident memory CD8+ T cells sustain frontline epithelial memory in the lung

Populations of CD8(+) lung-resident memory T (T-RM) cells persist in the interstitium and epithelium (airways) following recovery from respiratory virus infections. While it is clear that CD8(+) T-RM cells in the airways are dynamically maintained via the continuous recruitment of new cells, there is a vigorous debate about whether tissue-circulating effector memory T (T-EM) cells are the source of these newly recruited cells. Here we definitively demonstrate that CD8(+) T-RM cells in the lung airways are not derived from T-EM cells in the circulation, but are seeded continuously by T-RM cells from the lung interstitium. This process is driven by CXCR6 that is expressed uniquely on T-RM cells but not T-EM cells. We further demonstrate that the lung interstitium CD8(+) T-RM cell population is also maintained independently of T-RM cells via a homeostatic proliferation mechanism. Taken together, these data show that lung memory CD8(+) T-RM cells in the lung interstitium and airways are compartmentally separated from T-EM cells and clarify the mechanisms underlying their maintenance.