MHC Class I Molecules and Antigen Presentation Pathways

MHC class I molecules are cell-surface glycoproteins, expressed on virtually all nucleated cells, that display peptides derived mainly from proteins synthesised within the cell. By presenting these endogenous peptides to CD8+ cytotoxic T cells, they allow the immune system to detect cells that are infected by viruses or have become abnormal. The class I molecule is built from a polymorphic heavy chain paired with the invariant beta-2-microglobulin.

Definition

An MHC class I molecule is a heterodimer of a polymorphic transmembrane heavy chain and beta-2-microglobulin that binds short peptides (typically 8-10 residues) in a closed groove and presents them at the cell surface to CD8+ T cells.

Scope

This topic covers the architecture of the MHC class I molecule, the peptide-binding groove, the cytosolic (endogenous) loading pathway, and the role of class I in CD8+ T-cell surveillance. It is an educational reference on molecular immunology and does not address clinical typing or treatment.

Core questions

• How is the closed peptide-binding groove of class I built, and why does it favour short peptides?
• Where do the peptides presented by class I come from?
• How does class I presentation enable CD8+ T cells to detect intracellular infection?
• What role does beta-2-microglobulin play in class I assembly and stability?

Key concepts

• Heavy chain and beta-2-microglobulin
• Closed peptide-binding groove
• Endogenous (cytosolic) antigen pathway
• Proteasome and TAP-dependent peptide supply
• Peptide-loading complex
• CD8+ cytotoxic T-cell recognition
• Near-ubiquitous expression on nucleated cells

Mechanisms

The class I heavy chain folds into three extracellular domains; the membrane-distal alpha-1 and alpha-2 domains form a groove closed at both ends, which restricts bound peptides to roughly 8-10 residues anchored at their termini. Beta-2-microglobulin associates non-covalently to stabilise the fold. Peptides are produced in the cytosol, largely by the proteasome, and pumped into the endoplasmic reticulum by the transporter associated with antigen processing (TAP), where the peptide-loading complex assists assembly of stable peptide-MHC. The loaded molecule traffics to the surface, where a CD8+ T cell can engage it through its T-cell receptor and the CD8 co-receptor. The first crystal structure of HLA-A2 revealed this groove and the bound peptide density, and reviews integrate the supply pathway with class I assembly.

Clinical relevance

Class I presentation underlies cytotoxic T-cell responses to viruses and tumours and is relevant to transplantation, viral immune evasion, and tumour immunology. This entry explains the molecular pathway for educational purposes and is not a basis for individual diagnostic or therapeutic decisions.

Evidence & guidelines

The structural and pathway knowledge summarised here derives from landmark crystallography and from peer-reviewed immunology reviews and textbooks describing established cell biology rather than clinical guidelines.

History

Class I molecules were first defined as transplantation antigens, then linked to cytotoxic T-cell recognition through the MHC-restriction experiments of the 1970s. The 1987 crystal structure of HLA-A2 by Bjorkman and colleagues was a turning point, showing the peptide-binding groove directly and explaining how a single fold could present a vast diversity of peptides. Subsequent work mapped the proteasome-TAP-peptide-loading-complex pathway that supplies the groove.

Key figures

• Pamela Bjorkman
• Don Wiley
• Jack Strominger
• Peter Cresswell

Seminal works

• bjorkman-1987
• neefjes-2011
• blum-2013

Frequently asked questions

Which cells express MHC class I?

Almost all nucleated cells express MHC class I, which lets the immune system survey the internal protein content of nearly any cell in the body.

Why are class I peptides short?

The class I peptide-binding groove is closed at both ends, so it anchors a peptide at its termini and accommodates only short fragments, typically about 8-10 amino acids.