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

Takamura, Shiki

New definitions provided by intravascular staining Intravascular (i.v.) staining of cells in the bloodstream by i.v. injection with specific antibodies before harvesting the cells has revolutionized the analysis of lung T RM (5, 6) . Since the lung is a highly vascularized organ, it became apparent that a majority of CD8 + T cells purified from the lung tissues in earlier studies were contaminants from the blood. In fact, >95% of total CD8 + T cells in naive animals and *50% of antigen-specific memory CD8 + T cells in mice that had recovered from an influenza virus infection were found to be derived from the lung vasculature (6, 126) . Note that because the lung airways are segregated from the blood vessels, i.v. staining has essentially no impact on the cells in these tissues. However, a careful reinterpretation of previously published data regarding cells in the lung interstitium/parenchyma analyzed without i.v. staining is required. For instance, it has been reported that antigen-specific CD8 + T cells generated by intraperitoneal infections were efficiently recruited to the interstitium/parenchyma, but not to the lung airways when the effector T cell numbers peak (9-11 days) even in the absence of progressive infection or inflammation in the lung (122) . Furthermore, parabiosis experiments in which pairs of mice are surgically joined revealed that significant numbers of memory CD8 + T cells could also be recruited to the lung as up to half of the cells in this organ were replaced by circulatory CD8 + T cell populations (63, 84) . By using i.v. staining, those conclusions have been revised. First, although effector CD8 + T cells migrate into the interstitium of normal lungs more efficiently than naive CD8 + T cells (33) , the extent is much less than that observed in the presence of infection/inflammation in the lung (123) . Second, the migration of circulating memory CD8 + T cells to the lung under steady-state conditions is also relatively limited, as the ratio of new immigrants to resident cells never exceeds 20% (123) . On the basis of these new findings, we propose that the migration of effector as well as naive /memory CD8 + T cells into the noninflamed lung be termed as ''basal recruitment'' and be distinguished from ''active recruitment'': migration of antigen-specific effector CD8 + T cells to the lung in response to inflammation in the tissues (Fig. 1) . Strict discrimination between basal and active recruitment is important because tissue-derived instructive factors (e.g., antigen and inflammatory stimuli) that dictate T RM differentiation differs significantly depending on how the cells were recruited.