Type II pneumocyte-CD8+T-cell interactions - Relationship between target cell cytotoxicity and activation

CD8+ T-cell responses play an important role in the clearance of respirator y virus infection, but may also contribute to lung injury in the process. T he effector mechanisms involved in viral clearance and associated lung inju ry include both cytolytic and noncytolytic effector functions. Previously w e have shown that CD8+ T-cell recognition of alveolar epithelial cells trig gers chemokine expression by the epithelial cell and that this plays an imp ortant role in the inflammatory infiltration that ensues in the context of T cell-mediated injury (Zhao and colleagues, J. Clin. Invest. 2000;106:R49- R58). In the present study we sought to understand the relationship between alveolar cell cytotoxicity and chemokine expression, both of which occur a s a result of CD8+ T-cell antigen recognition. Alveolar epithelial cells ef ficiently process and present overlapping viral epitopes, and CD8+ T-cell r ecognition of these class I major histocompatibility complex-restricted epi topes resulted in cytotoxicity of the alveolar cells by both wild-type and perforin-deficient T cells. However, the contribution of perforin-mediated lysis to the total cytotoxicity of alveolar cells by CD8+ T cells was minim al, and the majority of the lysis was attributable to tumor necrosis factor -a expressed by the T cell. CD8+ T-cell recognition also led to activation of nuclear factor-kappaB in the alveolar epithelial target cells, at levels inversely proportional to the effector/target (E:T) ratio. Finally, at var ying E:T ratios, we demonstrated an inverse relationship between alveolar c ell cytotoxicity and monocyte chemotactic protein-1 expression, both of whi ch occur as a result of T-cell recognition. These findings may have importa nt ramifications in understanding the relationship between viral clearance and lung injury.