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

Takamura, Shiki

Integrin-mediated retention in the specific microenvironment of the lung In addition to CD69, high levels of integrin a1b1 (VLA-1: very late antigen-1) and aEb7 (detected by CD49a and CD103, respectively) expression are unique hallmarks of CD8 + T RM cells in the lung compared to circulatory memory CD8 + T cell populations in the lymphoid and nonlymphoid tissues, including T EM cells in the lung (123) . VLA-1 preferentially binds to type IV and type I collagen (40, 58, 128) . Type IV collagen constitutes the major structural component of basement membranes of the vascular endothelium and airway epithelium, while type I collagen is widely distributed in the lung interstitium (104) . In contrast, integrin aEb7 binds to E-cadherin, which forms adherens junctions between lung airway epithelial cells (98) . Analyses using blockade antibodies or knockout mice have revealed that both VLA-1 and integrin aEb7 are not required for the active recruitment of CD8 + T cells to the lung (74, 103) . Instead, these integrins fine-tune the distribution of migrant CD8 + T cells within the lung. For example, VLA-1 promotes distribution of cells in close proximity to the basement membranes of the blood vessels as well as the airways (103, 104) . The binding of VLA-1 to type IV collagen, in combination with signaling through tumor necrotic factor (TNF) receptor II, also protects effector CD8 + T cells in the airways from apoptosis during the acute phase of infection (105) . Interestingly, compared to effector CD8 + T cells, effector CD4 + T cells recruited to the lung exhibit lower VLA-1, but higher VLA-2 (integrin a2b1 detected by CD49b), which prefer type I, but not type IV collagen, allowing CD4 + T cells to localize preferentially in the lung interstitium, but not in the airways (104) . Integrin aEb7 also promotes retention of effector CD8 + T cells in the lung airways (51, 74) . It is important to note, however, that such integrin-mediated retention signals are likely redundant or supportive as the lack of one of those integrins does not lead to the significant loss of effector CD8 + T cells in the lung airways (74, 103) .