Review Article | Published:

Towards a systems understanding of MHC class I and MHC class II antigen presentation

Nature Reviews Immunology volume 11, pages 823836 (2011) | Download Citation


The molecular details of antigen processing and presentation by MHC class I and class II molecules have been studied extensively for almost three decades. Although the basic principles of these processes were laid out approximately 10 years ago, the recent years have revealed many details and provided new insights into their control and specificity. MHC molecules use various biochemical reactions to achieve successful presentation of antigenic fragments to the immune system. Here we present a timely evaluation of the biology of antigen presentation and a survey of issues that are considered unresolved. The continuing flow of new details into our understanding of the biology of MHC class I and class II antigen presentation builds a system involving several cell biological processes, which is discussed in this Review.

Key points

  • MHC class I and MHC class II molecules have long been intensively studied, and this has resulted in a global view of these processes. New technologies, including genome-wide small interfering RNA screens and systems biology approaches, have identified numerous additional pathways that control antigen presentation by MHC molecules.

  • MHC molecules are polymorphic, and the biology of the various alleles differs, such that they can potentially have different consequences with regards to the relevant immune responses. This point is best-defined for MHC class I molecules. In this Review, we bring this into context with the current understanding of the general MHC class I antigen presentation process.

  • The biology of MHC molecules touches almost all areas in the field of cell biology. Various new findings from the area of cell biology have consequences for MHC class I and MHC class II antigen presentation.

  • The immune system is a relatively late addition in our progress through evolution, and many immune-specific molecules exist. Unique functions of some of these, including the immunoproteasome in interferon-induced damage clearance, have been recently uncovered.

  • Through a combination of small interfering RNA screens, microarrays and cell biological approaches, novel pathways that control MHC class II expression and transport in dendritic cells have been defined. The systems biology of MHC molecules will yield more surprises.

  • A dynamic field of research has many unsolved issues. A survey of the views of almost 50 group leaders in the field of antigen presentation has provided democratic opinions on the variety of unsettled topics within the field.

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We thank our colleagues for their input in the controversial items section and I. Berlin, S. van Kasteren, O. Landsverk and A. Lammerts van Beuren-Brandt for critical reading. We apologize to our colleagues for not citing every relevant paper owing to length limitations. This work was supported by European Research Council (ERC) and Netherlands Organization for Scientific Research (NWO) grants to J.N. and an NWO visiting grant to O.B.

Author information


  1. Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

    • Jacques Neefjes
    • , Marlieke L. M. Jongsma
    •  & Petra Paul
  2. Centre for Immune Regulation, Department of Molecular Biosciences, University of Oslo, Norway.

    • Oddmund Bakke


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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jacques Neefjes.



The ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens onto MHC class I molecules. This property is atypical, because most cells exclusively present peptides from their endogenous proteins on MHC class I molecules. Cross-presentation is essential for the initiation of immune responses to viruses that do not infect antigen-presenting cells.


Any process involving delivery of a portion of the cytoplasm to lysosomes that does not involve direct transport through the endocytic or vacuolar protein-sorting pathways.


(Defective ribosomal products). Misfolded proteins that result from defective transcription or translation.

Cytotoxic T lymphocytes

(CTLs). T cells that express the glycoprotein CD8 at the cell surface and that are capable of killing cells after recognizing peptides presented by MHC class I molecules.

Pulse-chase experiments

A method to examine a cellular process that occurs over time by following a molecule of interest, which is labelled at time-point zero.

Mammalian target of rapamycin

(mTOR). A conserved serine/threonine protein kinase that regulates cell growth and metabolism, as well as cytokine and growth factor expression, in response to environmental cues. mTOR receives stimulatory signals from RAS and phosphoinositide 3-kinase downstream of growth factors and nutrients (such as amino acids, glucose and oxygen).


Small RNA molecules that regulate the expression of genes by binding to the 3′-untranslated regions of specific mRNAs.

26S proteasome

A giant multicatalytic protease that resides in the cytosol and the nucleus. The 20S core, which contains three distinct catalytic subunits, can be appended at either end by a 19S cap or an 11S cap. The binding of two 19S caps to the 20S core forms the 26S proteasome, which degrades polyubiquitylated proteins.

Thymic epithelial cells

(TECs). Cortical TECs promote the survival of thymocytes that possess T cell receptors that can bind to self MHC molecules. Medullary TECs induce apoptosis in thymocytes specific for self antigens.


An MHC-like molecule that acts as a chaperone in MHC class II peptide loading.


A subset of ribosomes that is thought to be responsible for the production of defective ribosomal products.

Crohn's disease

An inflammatory autoimmune disease of the gastrointestinal tract characterized by abdominal pain, vomiting and diarrhoea.


A member of a family of proteins that contain four transmembrane domains. Some tetraspanins are highly restricted to specific tissues, whereas others are widely distributed. Members of this family have been implicated in cell activation, proliferation, adhesion, motility, differentiation and cancer.

Endosomal sorting complex required for transport

(ESCRT). A complex of proteins required for the recognition and sorting of ubiquitin-modified proteins into the luminal vesicles of multivesicular bodies.


Small vesicles that are released from activated cells. They are bounded by a lipid bilayer that is derived either from the plasma membrane or from the membrane of internal vesicles of the MIIC.

Toll-like receptor

A member of a group of receptors that recognize components derived from a wide range of pathogens and switch on gene transcription that leads to cell activation and cytokine secretion.

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