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

lmmune-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 PeP-related IRD. [ABSTRACT FROM AUTHOR]