IFN- gamma and CD8 super(+) T Cells Restore Host Defenses Against Pneumocystis carinii in Mice Depleted of CD4 super(+) T Cells

Host defenses against infection are profoundly compromised in HIV-infected hosts due to progressive depletion of CD4 super(+) T lymphocytes and defective cell-mediated immunity. Although recent advances in antiretroviral therapy can dramatically lower HIV viral load, blood CD4 super(+) T lymphocytes are not restored to normal levels. Therefore, we investigated mechanisms of host defense other than those involving CD4 super(+) 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- gamma by gene transfer into the lung tissue results in clearance of PC from the lungs in the absence of CD4 super(+) lymphocytes. This resolution of infection was associated with a >4-fold increase in recruited CD8 super(+) T lymphocytes and NK cells into the lungs. The role of CD8 super(+) T cells as effector cells in this model was further confirmed by a lack of an effect of IFN- gamma gene transfer in scid mice or mice depleted of both CD4 super(+) and CD8 super(+) T cells. Cytokine mRNA analysis revealed that recruited, lung-derived CD8 super(+) T cells had greater expression of IFN- gamma message in animals treated with the IFN- gamma gene. These results indicate that CD8 super(+) T cells are capable of clearing PC pneumonia in the absence of CD4 super(+) T cells and that this host defense function of CD8 super(+) T cells, as well as their cytokine repertoire, can be up-regulated through cytokine gene transfer.