Altered Trained immunity in AID−/− versus wild type mice following infection with Pneumocystis murina

Abstract

Abstract Pneumocystis pneumonia continues to be a life-threatening infection in immunocompromised individuals. Dendritic cells are key antigen presenters to CD4+ T cells, which are critical to controlling Pneumocystis infection along with B cells. β-1,3 glucans are found in the cell wall of the cyst form of Pneumocystis. Glucans derived from other fungi have been shown to induce trained immunity. Therefore, we explored if Pneumocystis infection can induce a trained immunity response in C57Bl/6 (wild type) mice following exposure via a natural route of infection. We also tested activation-induced cytidine deaminase knockout mice (AID−/−), a deficiency that affects B cells, in the same infection model to determine whether a mutation known to affect the adaptive immune response can also alter the manifestation of trained immunity. We found that bone marrow derived dendritic cells (BMDCs) from C57BL/6 Pneumocystis exposed mice respond differently to homologous and heterologous antigen stimulation compared to BMDCs from naïve mice. Furthermore, although the differential response between cells from AID−/− exposed and naïve mice exists, specifically the TNFα response is opposite to that from C57BL/6 mice. In addition, when trained immunity was induced in BMDCs derived from naïve C57Bl/6 mice and AID−/− mice, the cytokine response was distinctive between the cells derived from C57BL/6 mice and AID−/− mice. These results suggest that not only can Pneumocystis infection induce trained immunity in BMDCs, this response is alterable by gene mutations traditionally thought to affect the adaptive immune response. Intramural Research Program of the NIH Clinical Center