Dissecting cross-presentation in dendritic cells: who, how and why?

ALLOATTI, ANDRÉS; MAGALHAES, JOAO; YATIM, NADER; KOZIK, PATRYCJA; CARPIER, JEAN-MARIE; JOANNAS, LEONEL; ALBERT, MATTHEW; AMIGORENA, SEBASTIAN

Whistler

Conferencia; Keystone Conference: "Cancer Vaccines: Targeting Cancer Genes for Immunotherapy"; 2016

Keystone Conferences

Phagocytosis in dendritic cells (DCs) mainly serves antigen processing and presentation on major histocompatibility complex (MHC) molecules. By contrast, macrophages and neutrophils use phagocytosis mostly for microbe destruction.While MHC class I presentation is classically restricted to endogenous antigens, exogenous antigens can also be presented on MHC I molecules in a process called cross-presentation, which is required for the initiation of cytotoxic immune responses specific for bacteria, tumor cell and viral antigen, as well as the maintenance of self tolerance. DCs have developed a specialized phagocytic pathway that optimizes conditions for cross-presentation.We have analyzed how Rab34 and Sec22b, two proteins involved in the membrane traffic across the phagocytic pathway, regulate antigen cross-presentation. The small GTPase Rab34 promotes accumulation of lysosomes in the perinuclear region to decrease phagosomal proteolytic capacity, resulting in enhanced cross-presentation. Importantly, this process can be regulated by toll-like receptor engagement. Regulating a distinct step in the pathway, Sec22b controls the delivery of ER‑resident proteins to phagosomes and the export of exogenous proteins from phagosomes to the cytosol. In order to evaluate the role of Sec22b in cross-presentation and the initiation of adaptive immune responses in vivo, we generated CD11c-conditional Sec22b-silenced mouse strain. These mice failed to mount effective CD8+ T cell responses specific for cell-associated antigen and failed to effectively control tumor growth. Our data suggests that silencing of Sec22b in DCs impairs cross-presentation both in vitro and in vivo.This work extends our understanding of the regulatory mechanisms that control cross-presentation as well as highlights the in vivo significance of antigen cross-presentation to mount efficient cytotoxic immune responses against microbes and tumors.