Memory-like innate immunity following infection with Pneumocystis murina

Abstract

Abstract Pneumocystis pneumonia (PCP) continues to be a life-threatening infection in HIV-infected patients, renal transplant patients, and other immunocompromised individuals. Dendritic cells are key antigen presenters to CD4+ T cells, which are critical to controlling Pneumocystis infection. b-1,3 glucans are found in the cell wall of the cyst form of Pneumocystis and are a known activator of innate immune cells via the dectin-1 receptor. b-glucans derived from other fungi have been shown to induce an enhanced “memory-like” immune response, termed trained immunity, in innate cells, including monocytes, macrophages, and dendritic cells. Therefore, we explored if Pneumocystis infection can induce an enhanced innate immune response in mice following exposure via a natural route of infection. We conducted mixing experiments using purified CD4+ T cells and dendritic cells from unexposed C57BL/6 mice and mice that spontaneously cleared infection. We found that CD4+ T cells from naïve mice exhibited a significantly greater proliferation after 5-day cultures when a crude Pneumocystis antigen was presented by CD11c+ dendritic cells from exposed mice compared to unexposed mice. In support of this, CD4+ T cells from C57BL/6 mice that were immunized with Freund’s adjuvant alone exhibited significantly greater proliferation when a crude Pneumocystis antigen was presented by either CD11c+ dendritic cells or CD11b+macrophages from mice immunized with Pneumocystis antigen mixed with Freund’s adjuvant vs. adjuvant alone. These results suggest that Pneumocystis infection stimulates a memory-like innate immune response which may be important in controlling subsequent exposure to Pneumocystis, as well as exposure to other pulmonary pathogens.