The relationship between protein dynamics and function for the MHC class I antigen presenting molecule (original) (raw)

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

Nature Reviews Immunology, 2011

We start with a description of the basic pathways, and then consider the recent advances in the field to arrive at a systems description of antigen presentation by MHC molecules. Furthermore, we have asked colleagues in the antigen processing and presentation field to provide their opinions on unresolved issues.

The ins and outs of MHC class II-mediated antigen processing and presentation

MHC class II-restricted antigen presentation is essential for CD4 + T cell-dependent immune responses. Different professional antigen-presenting cells (APCs) participate in a wide range of processes that are necessary for the generation of an effective and specific immune response. Dendritic cells (DCs) sample their environment and capture foreign antigens, such as those derived from bacteria or viruses, and initiate adaptive immune responses against these antigens by activating CD4 + and CD8 + T cells 1 . DCs and epithelial cells in the thymus express (and also capture) numerous self proteins and contribute to central tolerance and peripheral tolerance. By contrast, each B cell generally captures a single antigen after binding to its antigen-specific surface B cell receptor (BCR) 2 and then presents peptides from this antigen to specific T cells. Regardless of APC type, all APCs specifically interact with distinct subsets of T cells that express antigen-specific T cell receptors (TCRs) on their surface. The specificity of this interaction depends on the ability of APCs to display antigenic peptides, immobilized by MHC class I and class II molecules, on their surface. MHC class II binds antigenic peptides that are generated by proteolysis of self and non-self proteins in endosomes and lysosomes, and 'presents' them to antigen-specific CD4 + T cells 3 . Recognition of peptide-MHC class II by CD4 + T cells stimulates their activation and differentiation into T helper cell subsets Abstract | Antigenic peptide-loaded MHC class II molecules (peptide-MHC class II) are constitutively expressed on the surface of professional antigen-presenting cells (APCs), including dendritic cells, B cells, macrophages and thymic epithelial cells, and are presented to antigen-specific CD4 + T cells. The mechanisms of antigen uptake, the nature of the antigen processing compartments and the lifetime of cell surface peptide-MHC class II complexes can vary depending on the type of APC. It is likely that these differences are important for the function of each distinct APC subset in the generation of effective adaptive immune responses. In this Review, we describe our current knowledge of the mechanisms of uptake and processing of antigens, the intracellular formation of peptide-MHC class II complexes, the intracellular trafficking of peptide-MHC class II complexes to the APC plasma membrane and their ultimate degradation.

High efficiency of endogenous antigen presentation by MHC class II molecules

International Immunology, 1992

MHC class II molecules are Involved in the presentation of both exogenous and endogenous antigens to CD4 T cells. Using the trans-membrane hemagglutinin (HA) from measles virus and the secreted hen egg lysozyme (HEL) as antigen models, we have compared the efficiency of MHC class II presentation by naive antigen presenting cells (APCs) pulsed with exogenous antigen with that of their transfected counterparts synthesizing endogenous antigen. B cells expressing even a very low amount of trans-membrane HA were found to present endogenous HA to I-E d restricted T cell hybrldomas with a high efficiency whereas their naive counterparts required to be pulsed with a comparatively high amount of exogenous HA. Similarly, MHC class II presentation of endogenous secreted HEL was found to be much more efficient when compared with that of exogenous HEL. Biochemical studies did not reveal any enhanced intracellular degradation of endogenous HEL. As expected, HEL was released in the surrounding medium within <1 h. MHC class II presentation of endogenous HEL could not be explained by re-uptake by bystander APCs of HEL secreted In the surrounding medium. No sensitlzatlon of naive APCs could be observed either when co-cultured with HEL secreting cells or when cultured for 10 days with a sub-threshold amount of exogenous HEL. At the cell surface, I-E d molecules immunopreclpitated from HEL secreting cells were found to be slightly enriched In SDS-reslstant forms. These data raised the question of how peptides derived from endogenous transmembrane and secreted antigens can so efficiently reach an MHC class II loading compartment.

Peptide presentation by MHC class I molecules

Trends in cell biology, 1996

The presentation of peptides by class I histocompatibility molecules plays a central role in the cellular immune response to virally infected or transformed cells. The main steps in this process include the degradation of both self and 'foreign' proteins to short peptides in the cytosol, translocation of peptides into the lumen of the endoplasmic reticulum, binding of a subset of peptides to assembling class I molecules and expression of class-I-peptide complexes at the cell surface for examination by cytotoxic T cells. A molecular understanding of most of these steps is emerging, revealing a remarkable coordination between the processes of peptide translocation, delivery and binding to class I molecules.

Presentation of Cytosolic Antigens Via MHC Class II Molecules

Immunologic Research, 2004

Major histocompatibility (MHC) class II molecules function to present antigenic peptides to CD4 T lymphocytes. The pathways by which these molecules present exogenous antigens have been extensively studied. However by contrast, far less is known about the processing and trafficking of cytosolic antigens, which can also serve as an alternative source of ligands for MHC class II molecules. Self-proteins, tumor antigens, as well as viral proteins found within the cytosol of cells, can be presented via MHC class II molecules, resulting in the activation of specific CD4 T cells. Studies have begun to reveal unique steps as well as some similarities in the pathways for cytosolic and exogenous antigen presentation. Recent developments in this area are summarized here.