T Cytotoxic-1 CD8+ T Cells Are Effector Cells against Pneumocystis in Mice

Abstract

Host defenses are profoundly compromised in HIV-infected hosts due to progressive depletion of CD4+ T lymphocytes. A hallmark of HIV infection is Pneumocystis carinii (PC) pneumonia. Recently, CD8+ T cells, which are recruited to the lung in large numbers in response to PC infection, have been associated with some level of host defense as well as contributing to lung injury in BALB/c mice. In this study, we show that CD8+ T cells that have a T cytotoxic-1 response to PC in BALB/c mice, as determined by secretion of IFN-γ, have in vitro killing activity against PC and effect clearance of the organism in adoptive transfer studies. Moreover, non-T cytotoxic-1 CD8+ T cells lacked in vitro effector activity and contributed to lung injury upon adoptive transfer. This dichotomous response in CD8+ T cell response may in part explain the clinical heterogeneity in the severity of PC pneumonia.

Regulatory T Cells Dampen Pulmonary Inflammation and Lung Injury in an Animal Model ofPneumocystisPneumonia

“…It is also apparent that CD4 ϩ CD25 ϩ FoxP3 ϩ T cells are not effector cells against Pneumocystis. The role of CD8 T cells in organism clearance and lung injury associated with PCP is a complex issue with contradicting reports (13,35,36,38). Although further study is necessary to clearly define CD8 ϩ T cell responses, our data suggest there is a delayed injury response mediated by these cells as opposed to CD4 ϩ CD25 Ϫ T cells.…”

“…Previous studies from our laboratory have shown that reconstitution of Pneumocystis-infected SCID mice with nonpolarized CD8 ϩ cells is not sufficient to promote organism clearance (36). Although IFN-␥ levels in the lungs of animals reconstituted with CD4…”

“…Although Ab depletion of CD8 ϩ T cells in CD4-deplete animals results in more significant infection than depletion of CD4 ϩ cells alone (35), Pneumocystis-infected SCID mice reconstituted with CD8 ϩ T cells were unable to clear infection (7). However, adoptive transfer of CD8 ϩ cells isolated from AdIFN-treated animals to generate Tc1 cells resulted in decreased organism burden in the lungs of Pneumocystis-infected SCID mice (13,36). Furthermore, ␥␦-TCR ϩ T cell-deficient mice have augmented clearance of Pneumocystis associated with increased IFN-␥ producing CD8 ϩ T cells (37), suggesting the Tc1 subset of CD8 ϩ T cells are involved in host defense against Pneumocystis.…”

Sensitized CD8+T Cells Fail To Control Organism Burden but Accelerate the Onset of Lung Injury duringPneumocystis cariniiPneumonia

“…ϩ -T-cell-depleted mice from development of PCP (10,11,14). However, these interesting studies of the effect of gamma interferon addressed a different issue about the biology of CD8…”

“…In the gamma interferon studies the workers used mice that were challenged with P. carinii 24 h after transfection of lung cells with a gamma interferon gene (10,14) or 24 h before infusion of CD8 ϩ T cells isolated from mice that had been transfected with the gamma interferon gene (11). In these studies, gamma interferon-stimulated CD8 ϩ T cells protected against the development of PCP rather than controlled an established infection.…”