IFN-gamma and CD8(+) T cells restore host defenses against Pneumocystis carinii in mice depleted of CD4(+) T cells

Host defenses against infection are profoundly compromised in HIV-Infected hosts due to progressive depletion of CD4(+) T lymphocytes and defective ce ll-mediated immunity, Although recent advances in antiretroviral therapy ca n dramatically lower HIV viral load, blood CD4(+) T lymphocytes are not res tored to normal levels. Therefore, we investigated mechanisms of host defen se other than those involving CD4(+) T lymphocytes against a common HIV-rel ated opportunistic infection, Pneumocystis carinii (PC) pneumonia, Using CD 4-depleted mice, which are permissive for chronic PC infection, we show tha t up-regulation of murine IFN-gamma by gene transfer into the lung tissue r esults in clearance of PC from the lungs in the absence of CD4(+) lymphocyt es, 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-gamma gene transfer in acid mice or mice depleted of b oth CD4(+) and CD8(+) T cells. Cytokine mRNA analysis revealed that recruit ed, lung-derived CD8(+) T cells had greater expression of IFN-gamma message in animals treated with the IFN-gamma gene. These results indicate Chat CD 8(+) 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 t heir cytokine repertoire, can be up-regulated through cytokine gene transfe r.