The evolving biology of cross-presentation

Abstract

Cross-priming was first recognized in the context of in vivo cytotoxic T lymphocyte (CTL) responses generated against minor histocompatibility antigens induced by immunization with lymphoid cells. Even though the basis for T cell antigen recognition was still largely unclear at that time, these early studies recognized the implication that such minor histocompatibility antigens were derived from the immunizing cells and were obtained exogenously by the host's antigen presenting cells (APCs) that directly prime the CTL response. As antigen recognition by the T cell receptor became understood to involve peptides derived from antigens processed by the APCs and presented by major histocompatibility molecules, the "cross-priming" phenomenon was subsequently recast as "cross-presentation" and the scope considered for examining this process gradually broadened to include many different forms of antigens, including soluble proteins, and different types of APCs that may not be involved in in vivo CTL priming. Many studies of cross-presentation have relied on in vitro cell models that were recently found to differ from in vivo APCs in particular mechanistic details. A recent trend has focused on the APCs and pathways of cross-presentation used in vivo, especially the type 1 dendritic cells. Current efforts are also being directed towards validating the in vivo role of various putative pathways and gene candidates in cross-presentation garnered from various in vitro studies and to determine the relative contributions they make to CTL responses across various forms of antigens and immunologic settings. Thus, cross-presentation appears to be carried by different pathways in various types of cells for different forms under different physiologic settings, which remain to be evaluated in an in vivo physiologic setting.

Keywords: Antigen processing; Antigen uptake; Cross-presentation; Dendritic cells; Endosomes.

Fig. 1.

Model antigens and pathways of cDC1 cross-presentation. cDC1s cross-present many different forms of antigen, including soluble, cell-associated, microbe-associated, particulate, and antibody/immune complex, via several distinct mechanisms. In the ① Vacuolar Pathway, antigens in the phagosomes are processed into peptides by vesicular proteolytic enzymes such as CTSS. In the ② Cytosolic Pathway, antigens in the phagosomes are transported to the cytosol by various mechanisms such as membrane rupture via ROS-mediated lipid peroxidation triggered by CLEC9A signaling and activation of SYK and NADPH oxidase. Cytosolic antigens are then processed by proteasomes and either transported to the ER for classical MHC-I presentation (not depicted) or back to the phagosome by transporters such as TAP. In either pathway, MHC-I molecules stored in the RAB11A⁺ ERC traffic to the phagosomes in a TLR-dependent manner. TAP transporters and PLC traffic to the phagosomes from the ERGIC in a SEC22B-dependent manner. Together, peptides are loaded in the phagosomes and are transported to the cell surface for cross-presentation and cross-priming of CD8 T cells.

Fig. 2.

Mouse BEACH domain protein family. The domains of the nine BEACH domain proteins in mice are annotated and drawn to scale. The lighter shades within domains represent a short linker between two adjacent domains (e.g. PH-BEACH domains) or insertions unique to the subset of BEACH domain proteins (e.g. ARM). Domain boundaries were determined by protein structure prediction using I-TASSER [184] and RoseTTAFold [185]. Armadillo repeats (ARM); Concanavalin A-like lectin (ConA-ll); Pleckstrin homology-like (PH); Beige and Chediak-Higashi (BEACH); WD40 repeats (WD40); Fab1, YOTB, Vac1, and EEA1 (FYVE); Glucosyltransferases, Rab-like GTPase activators and myotubularins (GRAM).