BCG, the anti- tuberculosis vaccine localizes within immature phagosomes of macrophages and dendritic cells (APCs) and avoids lysosomal degradation. BCG-derived antigenic peptides are thus inefficiently processed by APCs, and we investigated alternate mechanisms of antigen processing. Proteomics identified that BCG phagosomes are enriched for nicastrin, APH and presenilin components of γ-secretase, a multimeric protease. Using an in vitro antigen presentation assay and BCG infected APCs, γ-secretase components were found to cleave BCG-derived antigen-85B to produce a peptide epitope, which in turn, primedIL-2 release from Ag85B-specific T cell hybridoma. siRNA knockdown or chemical inhibition of γ-secretase components using L685458, decreased the ability of BCG or M. tuberculosis infected APCs to present Ag85B. In addition, L685485 inhibition of γ-secretaseled to a decreased ability of BCG-DCs to immunize mice, and induce Ag85B-specific CD4 T cells in vivo. Since BCG and M. tuberculosis sequester within APCs preventing immune recognition, γ-secretase components appear to fortuitously process the immunodominant Ag85B, facilitating immune recognition.

No abstract

No abstract

No abstract

No abstract