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  • Review Article
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MHC-guided processing: binding of large antigen fragments

Nature Reviews Immunology volume 3, pages 621–629 (2003)Cite this article

An Erratum to this article was published on 01 October 2003

Key Points

  • Whether most MHC class II-bound ligands on the cell surface of antigen-presenting cells (APCs) arise from the binding of short peptides after degradative processing (cut first, bind later), or whether there are a considerable number of ligands that arise from initial binding of long polypeptides (bind first, cut later) in an early endosomal compartment, is still unresolved.

  • Most peptide cargo that can be eluted from MHC class II molecules is comprised of short peptides of 13–22 amino acids, each containing the core of the determinant and flanking ends of differing sizes. Yet, this result is also consistent with a bind first, cut later model.

  • In some cases long peptides have been reported to bind better than shorter peptides with the same determinant core and in the absence of further processing. This might be explained by postulating interactions between the long flanking ends of the determinant and sites on the MHC class II molecule that are distant from the peptide-binding groove. A prototype for such binding, for example, occurs with invariant chain (Ii), which makes numerous contacts with MHC class II molecules aside from the class II-associated Ii peptide (CLIP) region.

  • When native tightly folded antigens are reduced or cleaved with endopeptidases, those areas that are exposed during unfolding, which make initial strong contact with MHC class II molecules, will become dominant determinants. Flanking areas will be destroyed by exopeptidases and further enzyme processing, although distant, accessible areas on the antigen can bind to other MHC class II molecules. In this sense, the MHC class II molecule guides the processing.

  • The first cut, as carried out by several different endopeptidases, will greatly influence immunodominance, as the position of the cut will determine which neighbouring, previously invisible (or cryptic) determinant will gain exposure and have a chance to bind to the MHC class II peptide-binding groove.

  • Two MHC class II molecules of different allotypes can compete for distinct sites on a single antigen. After the binding of the first MHC class II molecule, the binding of the other might be hindered. So, the first MHC class II molecule carries out 'determinant capture' of what might become the dominant determinant, and the second MHC class II might be unable to bind a nearby determinant. The converse also occurs, 'competitive capture', in which several adjoining determinants compete for binding to the same MHC class II molecule.

  • The final peptide–MHC class II complex might arise in several ways, one of which involves stepwise degradation of Ii, protecting the MHC peptide-binding groove, until the final cleavage that leaves the residual CLIP (81–104) in the groove. After this, CLIP is replaced by local peptides with HLA-DM functioning as a catalyst. A second pathway involves the loss of Ii from MHC class II molecules in an early endosomal compartment and the preferential binding of long peptides that are derived from the native antigen.

  • The bind first, cut later pathway has much support and gives rise, with no further assumptions, to the multiplicity of peptides with the same core and ragged ends, as well as to the distinction between immunodominance and crypticity. It also predicts the types of competitive interaction in determinant capture and competitive capture.

Abstract

Ever since the emergence of models for the processing and presentation of antigenic determinants by MHC class II molecules, the main view has been that proteins are unfolded, enzymatically cleaved into peptide lengths of about 12–25 amino acids and then loaded onto MHC class II molecules. There is, however, an alternative model stating that partially intact unfolding antigens are first bound by MHC class II molecules and then trimmed to fragments of a smaller size while remaining bound to the MHC class II molecule. In this analysis, we make the case that a considerable portion of the elutable peptide cargo belongs to this latter class.

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Figure 1: MHC-guided processing and the role of proteolytic enzymes.
Figure 2: Competition between MHC class II molecules for antigen and vice versa.
Figure 3: Determinant capture in the response to HEL by NOD mice.
Figure 4: Invariant chain processing: is it comparable to antigen processing?
Figure 5: Two postulated pathways to final antigen presentation by MHC class II molecules.

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Acknowledgements

We would like to thank E. Thornes for help in producing this manuscript. The work in our laboratory was funded by grants from the National Institutes of Health, the Juvenile Diabetes Research Foundation and the National Multiple Sclerosis Society.

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Authors and Affiliations

  1. Torrey Pines Institute for Molecular Studies, San Diego, 92121, California, USA

    Eli E. Sercarz

  2. Harvard Medical School, Boston, 02115, Massachusetts, USA

    Emanual Maverakis

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Correspondence to Eli E. Sercarz.

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DATABASES

LocusLink

cathepsin L

cathepsin S

CD4

GILT

Glossary

MHC CLASS II DETERMINANT

A region on an antigen comprised of the same core residues that contact the MHC peptide-binding groove with various flanking residues. A determinant, in the strict sense, is the sequence that is required for recognition by a particular T cell.

IMMUNODOMINANT DETERMINANT

A determinant on a multi-determinant antigen that induces a response in antigen-primed cells, challenged in vitro with a peptide that contains the determinant.

PRO-DETERMINANT

The largest derivative of the whole antigen that can bind directly to a MHC class II molecule.

FUNCTIONALLY CRYPTIC DETERMINANT

Unlike the dominant determinant, the functionally cryptic determinant fails to induce a response in antigen-primed cells when challenged in vitro with peptides that contain the determinant.

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Sercarz, E., Maverakis, E. MHC-guided processing: binding of large antigen fragments. Nat Rev Immunol 3, 621–629 (2003). https://doi.org/10.1038/nri1149

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