A murine model of bone marrow transplant-related (BMT) lung injury was developed to study how infection sensitizes the lung to the damaging effects of total body irradiation (TBI) at doses of each that do not cause injury when given alone. Mice infected with Pneumocystis carinii (Pc) exhibited an asymptomatic, rapid, and transient increase in eosinophils and T cells in bronchoalveolar lavage fluid (BALF). In contrast, mice infected with Pc seven days prior to receiving TBI and syngeneic BMT (Pc/TBI mice) exhibited severe pulmonary dysfunction, surfactant aggregate depletion, and surfactant activity reductions at 17 days post-BMT. BALF from Pc/TBI mice contained a disproportionate initial influx of CD4⁺ T-cells (CD4⁺:CD8⁺ ratio of 2.7) that correlated with progressive lung injury (from 8 to 17 days post-BMT). Levels of TNF- in BALF were significantly increased in Pc/TBI mice compared to mice given either insult alone (P<0.0001), with peak values found at 11 days post-BMT. In vivo depletion of CD4⁺ T-cells in Pc/TBI mice abrogated pulmonary dysfunction and reduced TNF- levels in BALF, while depletion of CD8⁺ T-cells did not affect lung compliance or TNF-. Lung injury was not attributable to direct Pc damage, since CD4-depleted Pc/TBI mice that exhibited no injury had higher average lung Pc burdens than either mice given Pc alone or undepleted Pc/TBI mice. Taken together, these results indicate that Pc infection can sensitize the lung to subsequent TBI-mediated lung injury via a process dependent upon non-alloreactive CD4⁺ T-cells.