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

Takamura, Shiki

The T cell expression of S1P 1 is regulated by at least two distinct mechanisms: local cytokine-induced transcriptional downregulation of S1pr1, which encodes S1P 1 (115) , and the activation maker CD69-mediated posttranscriptional antagonism (8, 114) . Under the basal recruitment (in the absence of strong chemokine signaling in the tissues), forced expression of S1P 1 or genetic deletion of CD69 results in the significant loss of tissue-circulating CD8 + T cells as well as CD8 + T RM precursors in the nonlymphoid tissues, including the lung (78, 115, 123) , which is likely due to the accelerated tissue egress mediated by S1P 1 . Importantly, although pharmacological inhibition of S1P 1 by the agonist FTY720 leads to transient accumulation of CD69 -CD8 + T cells in the lung, this was reversed when FTY720 treatment was discontinued (123) . These findings suggest that T cells are committed to leave tissues during steady-state conditions, unless S1P 1 expression is inhibited. Since recruitment of CD8 + T cells into the lung does not lead to the downregulation of Klf2 or its downstream target S1pr1 (123), local reactivation and subsequent upregulation of CD69 are likely crucial for the temporal retention of tissue-circulating CD8 + T cells in the lung under the basal recruitment conditions (Fig. 1) . In contrast, we have demonstrated that this is not the case during the acute phase of infection where the lack of CD69 has a little impact on the active recruitment of effector CD8 + T cells to the lung unless a CD69-intact wildtype competitor T cell is present (123) . Thus, during the acute phase of infection, inflammation-induced chemotactic signaling overrides the S1P-mediated exit signal, which may explain the appearance of CD8 + T cells specific for unrelated antigens in the lung (23, 123) .