Major Histocompatibility Complex and Antigen Presentation

The major histocompatibility complex (MHC) is a cluster of highly polymorphic genes whose products display short peptide fragments on cell surfaces for inspection by T lymphocytes. In humans the locus is called the human leukocyte antigen (HLA) system. By presenting peptides derived from inside and outside the cell, MHC molecules let the adaptive immune system distinguish healthy self from infected, transformed, or foreign cells, and they underlie the discovery that T cells recognise antigen only in the context of self MHC.

Definition

The major histocompatibility complex is a genomic region encoding cell-surface glycoproteins (MHC class I and class II) that bind peptide antigens and present them to T-cell receptors, providing the molecular basis of MHC-restricted T-cell recognition.

Scope

This area orients the reader to the two principal classes of MHC molecule and the antigen-presentation pathways that load them, the genetics and extreme polymorphism of the locus, and the processing machinery (proteasome, TAP, endosomal proteases) that generates the peptides. It treats MHC as a reference topic in immunology, covering structure, function, genetics, and processing; it is not transplantation or clinical guidance.

Sub-topics

• Antigen Processing: Proteasomal and Endosomal Pathways
• MHC Class I Molecules and Antigen Presentation Pathways
• MHC Class II Molecules and Presentation to CD4+ Cells
• MHC Genetics, Polymorphism, and Disease Association

Core questions

• How do MHC class I and class II molecules acquire the peptides they display?
• Why is the MHC locus the most polymorphic region of the human genome, and what maintains that diversity?
• What does it mean for a T cell to be MHC-restricted?
• How do antigen-processing pathways feed peptides onto each MHC class?

Key concepts

• MHC class I and class II molecules
• Peptide-binding groove
• MHC restriction of T-cell recognition
• Human leukocyte antigen (HLA) system
• Polymorphism and codominant expression
• Endogenous versus exogenous antigen pathways
• Antigen-presenting cells

Key theories

MHC restriction

Zinkernagel and Doherty showed that cytotoxic T cells recognise viral antigen only when it is presented by the same MHC alleles the T cells matured with, establishing that T-cell recognition is restricted by self MHC rather than directed at free antigen.

Mechanisms

MHC class I molecules assemble in the endoplasmic reticulum and are loaded mainly with peptides generated in the cytosol by the proteasome and transported by TAP; they present to CD8+ T cells and are expressed on nearly all nucleated cells. MHC class II molecules are loaded in endosomal compartments with peptides from proteins captured from outside the cell and present to CD4+ T cells, with expression largely restricted to professional antigen-presenting cells. Each molecule carries a single peptide in a groove formed by polymorphic residues, so the set of peptides an individual can present is shaped by which HLA alleles they inherit. Neefjes and colleagues describe how the two pathways are integrated within the cell, and the structural basis of peptide display was established by the first MHC crystal structures.

Clinical relevance

MHC genes are central to transplantation matching, to many autoimmune and infectious-disease associations, and to how vaccines and tumours are recognised by T cells. The relationships described here explain why HLA type matters for compatibility and disease susceptibility; they are educational background on immune recognition and are not a basis for individual diagnosis, typing decisions, or treatment.

Evidence & guidelines

The conceptual framework rests on landmark experimental and structural work (the MHC-restriction experiments and the first crystal structures of class I and class II molecules) consolidated in major immunology reviews and textbooks. These describe established biology rather than clinical recommendations.

History

The MHC was first recognised through transplantation genetics in the mid-twentieth century, when tissue-rejection antigens were mapped to a single complex locus. Zinkernagel and Doherty's 1974 experiments reframed its function around T-cell recognition, showing that antigen is seen in the context of self MHC, a finding later recognised with the Nobel Prize. The crystal structures of HLA-A2 (Bjorkman et al., 1987) and HLA-DR1 (Brown et al., 1993) then revealed the peptide-binding groove and explained the molecular logic of presentation and polymorphism.

Key figures

• Rolf Zinkernagel
• Peter Doherty
• Pamela Bjorkman
• Don Wiley
• Jack Strominger
• Jan Klein

Seminal works

• zinkernagel-1974
• bjorkman-1987
• neefjes-2011
• trowsdale-2013

Frequently asked questions

What is the difference between MHC and HLA?

MHC (major histocompatibility complex) is the general term for the gene complex and its products across species; HLA (human leukocyte antigen) is the name for the human MHC specifically.

Why do MHC molecules matter for the immune system?

They display peptide fragments on the cell surface so that T cells can survey what proteins a cell is making or has taken up, which is how the adaptive immune system detects infected, abnormal, or foreign cells.