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

Takamura, Shiki

In the case of surface and mucosal tissues, such as skin and vagina, CD8 + T RM cells can be generated independent of cognate antigen. For example, forced recruitment of cells to the epithelial tissues by antigen-independent local inflammation or topical chemokine administration results in the establishment of CD8 + T RM cells (81, 113) , a method known as ''prime-pull.'' Furthermore, basal levels of CD8 + T RM cells can be deposited in multiple nonlymphoid tissues even after systemic infection in the absence of any local antigen presentation or inflammation (115, 119) . It should be noted that such bystander deposition of CD8 + T RM cells does not occur in the lung. As we have recently demonstrated, CD8 + T cells actively recruited to the lung by antigen-independent inflammation completely disappear after resolution of inflammation in the lung (123) . In contrast, the combination of local inflammation and cognate antigen successfully promotes lung CD8 + T RM cell development (123) . Thus, the lung is a unique tissue where local antigen is required for the establishment of CD8 + T RM cells. This appears to be based on the structural differences between lung and other surface/mucosal tissues, which will be discussed in detail later. Despite the fact that CD8 + T RM cells can be established in the skin independent of cognate antigen, there is a significant increase in the T RM formation when antigen is present (59, 97) , indicating that although local antigen recognition is not necessary for the establishment of T RM in all tissues, it nevertheless enhances T RM deposition. Hence, a second hit with cognate antigen in the 442 TAKAMURA peripheral tissues plays a key role not only for terminal effector differentiation but also function as pivotal tissue instruction for T RM differentiation. It is not understood how signals elicited by the local antigen can induce either terminal effector differentiation or T RM development. How is this decision checkpoint regulated? There are at least four potential explanations. First, the decision to become a terminal effector or T RM cell following local reactivation may be cell-intrinsically precommitted before recruitment, perhaps reflecting whether the cells originated from short-lived effector cells (SLECs) or memory precursor effector cells (MPECs) (57, 80) . Second, as previously described, a division of labor between respiratory DC subsets may also take place even within the lung, as CD103 + DCs, but not CD11b hi DCs, preferentially drive CD103 expression upon CD8 + T cell activation (133) . Third, fate decisions between terminal effector and T RM may be determined by temporal deviation of reactivation (16) . For example, in the case of CD4 + T cells, McKinstry et al. have shown that late antigen recognition, which is necessary for memory formation, occurred at days 5-8 postinfection, and have termed this time window as the ''memory check point'' (90) . Whereas a second hit for terminal effector differentiation may occur a little earlier, as cognate antigen-presenting respiratory DCs were transferred intranasally on day 3 and analyzed by day 5 (88) . Actually, this third hypothesis is mainly attributed to the fourth hypothesis in which effector versus memory fate decision may be regulated by the strength of CD8 + T cell activation. Both, the levels of antigen presentation (17) as well as the levels of the ''third signal'' induced by inflammatory cytokines (14) influence the activation status. Such