Endosomal processing for antigen presentation mediated by CD1 and Class I major histocompatibility complex: roads to display or destruction

Abstract

The presentation of antigen in a form that can be recognized by T lymphocytes of the immune system requires antigen processing and association of antigen-derived fragments with molecules encoded by the major histocompatibility complex (MHC) locus or by the CD1 locus. Much emphasis on antigen processing and presentation in the last decades has focused on what we consider 'conventional routes' of antigen processing and presentation, whereby extracellular antigens are processed for presentation via Class II MHC complexes and cytosolic antigens are presented as peptide-Class I MHC complexes. We here highlight two other pathways in myeloid dendritic cells, those of lipid antigen presentation in association with CD1 and of peptide cross-presentation via Class I MHC complexes. Some pathogens evade immune recognition through inhibition of antigen presentation of phagosomal origin. Deviations in endosomal antigen processing and presentation are also seen in individuals suffering from glycosphingolipid lysosomal lipid storage diseases. We summarize recent developments in the endosomal antigen processing and presentation pathway, for display as lipid-CD1 complexes to natural killer T cells and as peptide-Class I MHC complexes to CD8 T cells.

Figure 1

Intracellular distribution and trafficking of Class I major histocompatibility complex (MHC), Class II MHC and mouse CD1d (mCD1d) in maturing dendritic cells. Complexes are assembled in the endoplasmic reticulum (ER). To allow them to fold into functional complexes in the ER, chaperone molecules are co-assembled: antigenic peptide–Class I MHC; invariant chain–Class II MHC; and endogenous lipid–CD1d (i.e. phosphatidylinositol and glycosyl-phosphatidylinositol)., After arrival at the cell surface by routing through the secretory pathway, Class I MHC display and CD1d molecules recycle through early endocytic compartments, from where CD1d molecules are sorted to late endocytic/lysosomal compartments for exchange of ER-derived lipid for antigenic lipid cargo. Most nascent invariant chain–Class II MHC complexes arrive in the endosomal pathway directly from the Golgi system for acquisition of antigenic peptide. Chaperone proteins can facilitate antigen loading in the ER (Class I loading complex for Class I MHC and some processes of CD1d assembly, and lipid transfer proteins for lipid loading) and in the endosomal pathway (H2-DM for Class II MHC , and lipid transfer proteins for mCD1d).,, Maturation of DCs rearranges intracellular trafficking to promote the presentation of newly acquired antigen from ER or endosomes at the cell surface, for inspection by appropriately restricted T cells. Arrow thickness represents the relative rate of translocation of Class I MHC, Class II MHC and mCD1d complexes. β2m, beta-2-microglobulin.