Early phagocytic compartments play a role in protein sorting, signaling and neutralizing pathogens. In addition, certain subsets of dendritic cells (DCs) load peptides derived from exogenous antigens on to MHC class-I molecules in early phagosomes. This process plays a key role in antigen cross-presentation, a process particularly important in the activation of naïve CD8+ T-cells when it is known as cross-priming and is essential for mounting an immune response against tumor and viral antigens. The functional properties of early phagosomes that facilitate cross-presentation remain unclear. Here we show that the expression of Rab GTPase mutants (Rab5CA, Rab7DN and Rab22CA) that impair maturation of phagosomes enhance antigen cross-presentation efficiency of DCs as well as an engineered derivative of 293T cells capable of cross-presentation. Enhanced antigen cross-presentation observed upon expression of the Rab5CA, Rab7DN and Rab22CA mutants remains dependent on proteasome activity. However, expression of the mutants renders cross-presentation independent of the activity of Transporter associated with antigenic peptide (TAP). These findings taken together reveal a novel TAP independent but proteasome dependent mechanism of MHC class I-restricted antigen processing and peptide loading that is facilitated by slow maturation of endocytic compartments.
Citation Format: Debrup Sengupta, Peter Cresswell. Slow maturation of early phagosomes promotes a TAP independent antigen cross-presentation pathway. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B059.
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