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

Abstract

While CD8؉ cells have been shown to contribute to lung injury during Pneumocystis carinii pneumonia (PCP), there are conflicting reports concerning the ability of CD8 ؉ cells to kill P. carinii. To address these two issues, we studied the effect of the presence of CD8 ؉ cells in two mouse models of PCP. In the reconstituted SCID mouse model, depletion of CD8؉ cells in addition to CD4 ؉ cells after reconstitution did not result in increased numbers of P. carinii cysts compared to the numbers of cysts in mice with only CD4 ؉ cells depleted. This result was observed regardless of whether the mice were reconstituted with naïve or P. carinii-sensitized lymphocytes. In contrast, reconstitution with sensitized lymphocytes resulted in more rapid onset of lung injury that was dependent on the presence of CD8؉ cells. The course of organism replication over a 6-week period was also examined in the CD4؉ -T-cell-depleted and CD4 ؉ -and CD8 ؉ -T-cell-depleted mouse model of PCP. Again, the organism burdens were identical at all times regardless of whether CD8؉ cells were present. Thus, in the absence of CD4 ؉ T cells, CD8 ؉ T cells are a key contributor to the inflammatory lung injury associated with PCP. However, we were unable to demonstrate an in vivo effect of these cells on the course of P. carinii infection. Efficient control of Pneumocystis carinii infection requires normally functioning CD4ϩ T cells (9, 12). Although CD8 ϩ T cells have been reported to be able to produce a modest decrease in the level of P. carinii infection in the absence of CD4 ϩ T cells (2), the mechanism for this effect is not obvious since P. carinii is, as far as we know, an extracellular pathogen. Our observations have failed to demonstrate any killing of P. carinii by CD8 ϩ T cells (16; unpublished observations). On the other hand, there is clear evidence that CD8 ϩ T cells make a biologically significant contribution to the immune-mediated inflammatory insult to the lung during P. carinii pneumonia (PCP) (16,17). Therefore, defining the contribution of CD8 ϩ T cells to the control of infection compared to the exacerbation of lung injury is important in developing improved adjunctive therapies for PCP targeted at suppressing CD8 ϩ T cells. To more precisely define the role of CD8 ϩ T cells in the control of P. carinii f. sp. muris, we carried out a series of experiments with two mouse models of PCP. Using the immune reconstituted SCID mouse model, we hypothesized that if CD8 ϩ T cells can in fact kill P. carinii, then exposure (i.e., sensitization) of CD8 ϩ T cells to P. carinii by immunization before they are infused into P. carinii-infected SCID mice should result in enhanced clearance of organisms. Using donor splenocytes from P. carinii-immunized mice also allowed us to further examine the effect of CD8 ϩ T cells on immune-mediated inflammatory injury during PCP. With regard to the latter point, we hypothesized that if CD8 ϩ T cells play a key role in initiating the inflammatory response during PCP, then CD8 ϩ T cells from immunized donor ...

Treatment with Interleukin-7 Restores Host Defense against Pneumocystis in CD4+T-Lymphocyte-Depleted Mice

“…We did not observe any increased cellular pathology associated with increased levels of CD8 ϩ T cells following treatment with rhIL-7. However, others have reported that CD8 ϩ T cells have little importance in the control of P. murina (42). In support of a protec- tive role for CD8 ϩ T cells, we found in this study that systemic administration of rhIL-7 induces the proliferation and activation of CD8 ϩ T cells independently of CD4 ϩ T cells and that this treatment provided enhanced resistance against P. murina infection.…”

Decreased inflammatory response in Toll-like receptor 2 knockout mice is associated with exacerbated Pneumocystis pneumonia

“…[19] A recent study showed that sensitized CD8+ T cells fail to clear organisms but accelerate the onset of lung injury during PcP. [20] In this study, we found that the numbers of neutrophil and monocyte/macrophage were decreased in TLR2−/− mice with PcP and the number of CD8+ T cells in the lungs of TLR2−/− mice with PcP was found to be similar to that of wild type mice with PcP. These results suggest that neutrophil and monocyte/macrophage play a role in TLR2-mediated inflammatory response during PcP.…”

Characterization of a Distinct Host Response Profile to Pneumocystismurina Asci during Clearance of Pneumocystis Pneumonia

“…The CD4 ϩ T cell responses have long been considered essential for the prevention of PcP and play a major role in its resolution by orchestrating the activities of adaptive immunity through interaction with other cells, production of cytokines, and enhancing antibody production (51). In the absence of CD4 ϩ T cells, CD8 ϩ T cells become the prominent immune cell type detected in the lung and are often associated with a failure to control the infection with a concomitant deleterious inflammatory response leading to lung damage, although they have also been implicated in a beneficial host response (52,53). The results presented here suggest that P. murina asci promote migration of CD8 ϩ T cells to the lung and prolong the T cell pulmonary response.…”