Contribution of T cell subsets to the pathophysiology ofPneumocystis-related immunorestitution disease

Abstract

Immune-mediated lung injury is an important component of Pneumocystis pneumonia (PcP)-related immunorestitution disease (IRD). However, the individual contribution of CD4+and CD8+T cells to the pathophysiology of IRD remains undetermined. Therefore, IRD was modeled in severe combined immunodeficient mice, and specific T cell depletion was used to determine how T cell subsets interact to affect the nature and severity of disease. CD4+cells were more abundant than CD8+cells during the acute stage of IRD that coincided with impaired pulmonary physiology and organism clearance. Conversely, CD8+cells were more abundant during the resolution phase following P. carinii clearance. Depletion of CD4+T cells protected mice from the acute pathophysiology of IRD. However, these mice could not clear the infection and developed severe PcP at later time points when a pathological CD8+T cell response was observed. In contrast, mice depleted of CD8+T cells efficiently cleared the infection but developed more severe disease, an increased frequency of IFN-γ-producing CD4+cells, and a prolonged CD4+T cell response than mice with both CD4+and CD8+cells. These data suggest that CD4+T cells mediate the acute respiratory disease associated with IRD. In contrast, CD8+T cells contributed to neither lung injury nor organism clearance when CD4+cells were present, but instead served to modulate CD4 function. In the absence of CD4+cells, CD8+T cells produced a nonprotective, pathological immune response. These data suggest that the interplay of CD4+and CD8+T cells affects the ultimate outcome of PcP-related IRD.