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_EM 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.