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and CD8+ T Cells Restore Host Defenses Against Pneumocystis carinii in Mice Depleted of CD4+ T Cells1
,
,
*
Section of Pulmonary/Critical Care,
Gene Therapy Program, and
Section of Hematology/Oncology, Louisiana State University Medical Center School of Medicine, New Orleans, LA 70112
Host defenses against infection are profoundly compromised in
HIV-infected hosts due to progressive depletion of CD4+ T
lymphocytes and defective cell-mediated immunity. Although recent
advances in antiretroviral therapy can dramatically lower HIV viral
load, blood CD4+ T lymphocytes are not restored to normal
levels. Therefore, we investigated mechanisms of host defense other
than those involving CD4+ T lymphocytes against a common
HIV-related opportunistic infection, Pneumocystis
carinii (PC) pneumonia. Using CD4-depleted mice, which are
permissive for chronic PC infection, we show that up-regulation of
murine IFN-
by gene transfer into the lung tissue results in
clearance of PC from the lungs in the absence of CD4+
lymphocytes. This resolution of infection was associated with a
>4-fold increase in recruited CD8+ T lymphocytes and NK
cells into the lungs. The role of CD8+ T cells as effector
cells in this model was further confirmed by a lack of an effect of
IFN- gene transfer in scid mice or mice depleted of
both CD4+ and CD8+ T cells. Cytokine mRNA
analysis revealed that recruited, lung-derived CD8+ T cells
had greater expression of IFN- message in animals treated with the
IFN- gene. These results indicate that CD8+ T cells are
capable of clearing PC pneumonia in the absence of CD4+ T
cells and that this host defense function of CD8+ T cells,
as well as their cytokine repertoire, can be up-regulated through
cytokine gene transfer.
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