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

Takamura, Shiki

As discussed above, cognate antigen that remains in the RAMDs is also a potential factor regulating the number of CD8 + T RM cells in the lung. In fact, viral antigen can be detected in the peribronchiolar lymphocytic infiltrates (62) as well as bronchial epithelial cells (41) at least a month postinfection. Furthermore, CD8 + T RM cells, but not T EM cells, express CD69 as well as PD-1, indicative of recent activation (123, 135) . Those observations suggest that residual antigen presentation is limited in the RAMDs, but not in the unaffected lung interstitium. Thus, the reduced CD8 + T RM persistence in the RAMDs is also potentially caused by reduction in the level of residual antigen presentation. Importantly, despite the fact that PD-1 impairs the protective efficacy of memory CD8 + T cells in the lung (28, 92) , accumulating evidence suggests that these cells never succumb to functional exhaustion (25, 44) . Thus, the level of residual antigen presentation must be lower than that exhibited during a typical chronic infection. In line with this, PD-1 as well as other potential inhibitory molecules may act to prevent excessive immunopathology (26, 27, 29) by maintaining the cells in a quiescent state (49) . Furthermore, reactivation of CD8 + T RM cells in the lung leads to sustained expression of interferon-induced transmembrane protein (IFITM3), which is involved in conferring resistance against subsequent virus infection (132) . Hence, in contrast to chronic infection, the repeated acquisition of weak cognate signals may be beneficial rather than harmful for the maintenance of CD8 + T RM cells in the lung. A remaining question is how APCs avoid being eliminated by antigen-specific CD8 + T RM cells. It is tempting to hypothesize that PD-1-mediated partial inhibition may play a role in this escape without inducing the global exhaustion.