Class II MHC antigen processing in immune tolerance and inflammation

Abstract

Presentation of peptide antigens by MHC-II proteins is prerequisite to effective CD4 T cell tolerance to self and to recognition of foreign antigens. Antigen uptake and processing pathways as well as expression of the peptide exchange factors HLA-DM and HLA-DO differ among the various professional and non-professional antigen-presenting cells and are modulated by cell developmental state and activation. Recent studies have highlighted the importance of these cell-specific factors in controlling the source and breadth of peptides presented by MHC-II under different conditions. During inflammation, increased presentation of selected self-peptides has implications for maintenance of peripheral tolerance and autoimmunity.

Keywords: Antigen presentation; Immunopeptidome; MHC protein; Major histocompatibility complex.

Conflict of interest statement

Conflict of Interest

The authors declare that they have no conflict of interest.

Figures

Figure 1:

MHC Class II dimers are synthesized in the ER and loaded with invariant chain, after which they traffic to the endosome. Cathepsins cleave the invariant chain (Ii) to the residual peptide CLIP, which is then removed by the peptide exchange factor DM and exchanged for peptides derived from proteolyzed self- and foreign antigens. The MHC-II-peptide complex traffics to the cell surface for presentation to CD4 T cells. To maintain tolerance in noninflammatory conditions (left panel), the immunopeptidome in APCs is comprised of diverse self-peptide antigens acquired through extracellular uptake pathways as well as autophagy. Components of the antigen processing machinery including the DM inhibitor DO further enhance the diversity of the peptides presented. Upon activation and initiation of an inflammatory response (right panel), antigen sampling is reduced, endosomal proteases are redistributed to late endosomes, DO expression is downregulated, and MHC-II expression is substantially increased. (The effects of inflammation on the process of autophagy in APCs are incompletely understood.) During inflammation, these changes result in greater efficiency of MHC-II antigen presentation as well as reduced diversity in the MHC-II peptidome in an immune response.