Beryllium activates innate pattern recognition receptors, promotes migration and activation of dendritic cells from the lung to draining lymph nodes and drives development of memory CD4 T cells (P3129)

Abstract

Abstract Beryllium exposure results in chronic beryllium disease, a granulomatous lung disorder characterized by the presence of a beryllium-specific adaptive immune response. The impact of beryllium on the innate immune system is poorly understood. The aim of this study was to determine whether beryllium promotes activation of innate pattern recognition receptors that drive the development of pathological CD4 T cell responses. Similar to aluminum hydroxide, a common vaccine adjuvant, beryllium particles induce IL-1β secretion in an Nlrp3-dependent manner and the release of host DNA during inflammation. Unlike aluminum, beryllium-induced IL-1β secretion requires TLR4. A single beryllium exposure in the lungs of mice promotes migration of DCs to the draining lymph nodes and upregulation of DC costimulatory molecules in a MyD88-dependent manner. Beryllium enhances priming and maintenance of memory CD4 T cells to conventional protein antigen and can generate beryllium-specific CD4 T cell responses in HLA-DP2 transgenic mice in the absence of an additional adjuvant. Together, these data suggest that beryllium activates multiple innate immune receptors and promotes pathological immune responses in susceptible individuals by promoting activation of DCs that drive long-lived CD4 T cell responses. Future work is aimed at understanding which innate receptors are required for beryllium to activate DC in vivo and drive CD4 T cell effector and memory function.