Persistence in Temporary Lung Niches: A Survival Strategy of Lung-Resident Memory CD8(+) T Cells

Takamura, Shiki

In the case of skin, CD8 + T RM precursors recruited to the skin persist in an epidermal niche that is originally occupied by dendritic epidermal cd T cells (DETCs). This results in their lifelong persistence (137) . Because normal lung tissues do not exhibit such preformed niches to displace, additional ''space'' is required for the cells to inhabit. It has long been believed that lung CD8 + T RM cells are maintained in the ectopic lymphoid tissues developed in response to respiratory virus infections, such as inducible bronchus-associated lymphoid tissues (iBALT) (95) . However, our group has demonstrated that such structures are primarily populated with CD4 + T cells as well as B cells, but relatively few numbers of CD8 + T cells (123) . Rather, CD8 + T RM cells are enriched specifically in niches created at the site of tissue regeneration after injury, which are termed as repair-associated memory depots (RAMDs) (123) . Histologically, RAMDs represent confluent foci of peribronchiolar lymphocytic infiltrates with diffuse thickening of alveolar walls in surrounding area. Thus, the niches exist primarily in the lung interstitium with partial extension to the lung parenchyma. The appearance of cytokeratin-expressing cell aggregates, known as Krt pots, is a unique hallmark of RAMDs. Krt pots comprise distal airway stem cells that begin to emerge in the lung around day 7 postinfection, proliferate vigorously, and subsequently differentiate and reconstruct the damaged lung tissues (68, 129, 140) . However, it is unclear whether those cells directly impact the differentiation of CD8 + T RM cells. CD8 + T RM cells in the RAMDs do not form a specific organized structure and are simply sequestered in this site, while CD4 + T RM cells in the iBALT typically form clusters and surround B cell follicles (123) . Such distinct distributions between CD8 + and CD4 + T RM cells in the lung clearly reflect their division of labor upon recall, in which CD8 + T RM cells exert their function as cytotoxic T lymphocytes (CTLs) at the damaged site, while CD4 + T RM cells and B cells need to interact with each other in the iBALT for sustained germinal center formation (3). There is also rigid compartmentalization between lung CD8 + T RM cells and CD8 + T EM cells that circulate between the lung and blood. For instance, CD8 + T EM cells in the lung are widely, but sparsely distributed in the unaffected lung interstitium, and never involved in the RAMDs unless de novo niches are newly created (123) . As described previously, CD8 + T EM cells exit lung tissues mainly through S1P-induced chemotaxis to the lymph. In contrast, inhibition of S1P 1 is no longer required for the retention of CD8 + T RM cells in the RAMDs due, in part, to limited access to S1P gradient in this microenvironment (123) . Importantly, not only tissue-circulating CD8 + T EM cells but also effector CD8 + T cells are incapable of being involved in the RAMDs later than the peak of CD8 + T cell response in the lung (around day 10, which also reflects the peak of tissue damage) (123) . Because administration of cognate antigen in combination with the prime-pull strategy enables de novo creation of the RAMD and subsequent establishment of CD8 + T RM cells in the lung (123) , the availability of cognate APCs in the RAMDs likely restricts the numbers of CD8 + T cells deposited. Indeed, there is a competition among antigen-specific effector CD8 + T cells to interact with cognate APCs in the inflamed