STAT4 deficiency impairs CD4 T cell responses, yet enhances pathogen-specific antibody production during Pneumocystis murina lung infection (70.7)

Abstract

Abstract Although it is clear that the loss of CD4+ T cells is a predisposition to Pneumocystis pneumonia, the underlying mechanism for host defense is not well understood. Mice deficient in IFN-αR, IL-12p35, or IL-23p19 have delayed clearance of Pneumocystis murina, all of which activate the pro-Th1 transcription factor STAT4. In order to investigate the role of STAT4 in host defense against P. murina, C57BL/6 wild-type (WT) and STAT4-/- mice were infected intratracheally with P. murina cysts and fungal burden was assessed 28 days later. Despite a reduction in the total number of leukocytes in the lung on day 14 after infection in STAT4-/- mice, P. murina clearance at day 28 was not affected by the absence of STAT4. On day 14 after P. murina infection, STAT4-/- mice showed increased production of the Th2-type cytokine IL-5 relative to WT mice. In addition to CD4+ T cells, humoral immune responses are also critical for the clearance of P. murina, and because IL-5 has been shown to be important in antibody (Ab) production, we examined pathogen-specific Ab production in WT and STAT4-/- mice. STAT4-deficient mice had increased production of anti-P. murina IgG1, IgG2b, and IgG2c leading to enhanced opsonic killing by alveolar macrophages ex vivo compared to serum of WT mice. These data suggest that increased anti-P. murina Ab production, which enhances alveolar macrophage-mediated killing, may overcome T cell defects in the absence of STAT4, resulting in unimpaired clearance of P. murina.