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--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 non-protective, pathological immune response. These data suggest that the interplay of CD4⁺ and CD8⁺ T cells affects the ultimate outcome of PcP-related IRD.