Role of CD8+ lymphocytes in host defense against Pneumocystis carinii in mice

Abstract

An improved understanding of host defense against Pneumocystis carinii could provide novel therapeutic modalities directed against this opportunistic pathogen. Immunodeficient mouse models confirm the role of CD4+ lymphocytes in defense against P. carinii, but the role of CD8+ lymphocytes is controversial. BALB/c mice specifically depleted of CD4+ lymphocytes are susceptible to P. carinii, recruiting large numbers of CD8+ lymphocytes to their lungs during infection. Because of this recruitment, we hypothesized that CD8+ lymphocytes could participate in host defense against P. carinii. BALB/c mice were depleted of CD4+ lymphocytes, CD8+ lymphocytes, or both CD4+ and CD8+ lymphocytes. All mice were then inoculated intratracheally with P. carinii. Mice depleted of CD4+ lymphocytes became moderately infected with P. carinii. Mice depleted of CD8+ lymphocytes cleared the inoculum, indicating that CD8+ lymphocytes are unnecessary for defense when CD4+ lymphocytes are available. However, mice depleted of both CD4+ and CD8+ lymphocytes became significantly more intensely infected than mice depleted of CD4+ lymphocytes alone. Therefore, CD8+ lymphocytes participate in defense against P. carinii in vivo during depletion of CD4+ lymphocytes. To determine the mechanisms of this protection, CD8+ lymphocytes were purified from the lungs of CD4-depleted mice during infection. Lung CD8+ lymphocytes proliferated in response to P. carinii antigen and elaborated interferon-gamma in vitro. Thus CD8+ lymphocytes provide defense against P. carinii in vivo, and the elaboration of interferon-gamma likely represents one important mechanism of defense. During states of CD4+ lymphocyte depletion, the modulation of CD8+ lymphocyte function may provide alternative approaches to the host defense against opportunistic pathogens.