Cross-presentation of exogenous antigens on MHC I molecules

Abstract

In order to get recognized by CD8 T cells, most cells present peptides from endogenously expressed self or foreign proteins on MHC class I molecules. However, specialized antigen-presenting cells, such as DCs and macrophages, can present exogenous antigen on MHC-I in a process called cross-presentation. This pathway plays key roles in antimicrobial and antitumor immunity, and also immune tolerance. Recent advances have broadened our understanding of the underlying mechanisms of cross-presentation. Here, we review some of these recent advances, including the distinct pathways that result in the cross-priming of CD8 T cells and the source of the class I molecules presenting exogenous peptides.

Figure 1. Cross-Presentation Pathways.

Professional antigen presenting cells internalize exogenous antigens into phagosomes and endosomes. In dendritic cells, Nox2 is recruited (blue) and produces ROS, which then results in an increase in endocytic pH and a reduction in proteolytic hydrolysis. (A) Antigen may escape into the cytosol (P2C pathway) through channels found on endosomes/phagosomes (perhaps via an ERAD-like mechanism) or (B) due to rupture of phagosomal membranes. Once in the cytosol antigen is targeted for degradation by the ubiquitin-proteasome pathway and the resulting peptides are then translocated via TAP transporters on the ER or (C) endocytic compartments (P2C2P pathway). (D) Some antigens remain within the vacuolar compartment (vacuolar pathway) where peptides are cleaved by hydrolytic proteases (e.g. cathepsin S) and loaded on MHC I molecules. Peptide-MHC I complexes then transit to the PM for recognition by CD8+ T cells. Dashed lines with arrows indicate incompletely understood or postulated aspects in the pathway. Abbreviations: PM: plasma membrane, ER: endoplasmic reticulum, ERGIC: ER-golgi intermediate compartment, PLC: peptide loading complex.

Figure 2:. Source of MHC I in phagosomes.

(A) Class I molecules may traffic from the PM following ARF6-mediated internalization or phagocytosis. (B) Class I molecules may be stored in the endosomal recycling compartment following a UCH-L1-depedent deubiquitination step. TLR activation results in a phospho-SNAP-23-dependent fusion of these vesicles with the phagosome. Alternatively, newly synthesized class I molecules may traffic directly to the endocytic compartment via Rab39a-mediated vesicle transport (C) or chaperoned by the invariant chain (brown) (D). (E) Another pathway involves transport from the TGN to endosomes that is dependent on MARCH9-mediated ubiquitination. Dashed lines with arrows indicate incompletely understood aspects in the pathway. Abbreviations: EE: early endosomes, TLR: toll-like receptor