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Antigen Presentation Overview

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The mechanism/process by which T cells are activated through their antigen receptors by Major Histocompatibility Complex (MHC) molecules loaded with antigenic peptides on the surface of cells is called antigen presentation. There are two distinct canonical forms of antigen presentation: one involving the presentation of peptides bound to Class I MHC molecules to CD8 T cells; the other involving the presentation of peptides bound to Class II MHC molecules to CD4 T cells. T cell antigen receptors (TCRs) recognize small peptide fragments of antigens bound to self MHC molecules on the surface of autologous or syngeneic cells but not allogeneic cells. The requirement for the binding of peptides in the context of self-MHC molecules is known as MHC restriction. While the CD8 and CD4 accessory molecules do interact with the respective MHC molecules, it is the TCRs themselves that are responsible for MHC restriction. TCRs on CD8 T cells are selected during development to respond to peptides bound to class I MHC and TCRs on CD4 T cells to peptides on Class II MHC molecules.

The ability to present antigens to T cells requires that a cell, the antigen-presenting cell (APC), be able to (1) express MHC molecules on their surface, (2) convert an antigenic protein into small peptides, (3) load an appropriate MHC molecule with the peptide, and (4) transport the loaded MHC molecules to the cell surface where they can be engaged by a TCR (5). The mechanism of loading class I MHC molecules differs from that of class II molecules based largely on where the proteins come from. Proteins destined for class I presentation are synthesized inside the cell, while those destined for class II presentation are synthesized exogenously and brought into the cell via endocytosis.

All cells express class I MHC molecules, and thus have the ability for class I MHC antigen presentation. With presentation via the class I pathway, proteins produced inside the cell, such as viral proteins in an infected cell or mis-formed endogenous proteins, are degraded by complex cytosolic structures called proteasomes. Proteasomes act like tiny wood chippers shredding proteins into small peptides of specific sizes. The peptides are then translocated into the lumen of the Endoplasmic Reticulum (ER) via the Transporter associated with Antigen Processing (TAP) structure. In the ER lumen the peptides are loaded onto newly synthesized MHC class I molecules with the aid of TAP-associated glycoprotein (Tapasin) and transported to the cell surface via the ER/Golgi system.


Antigen cross-presentaiton

Antigen Presentation Table

MHC Class I (HLA-A, B, C in Humans; H2 D, K, L in mice)
Expressed on: all cells
Presents to: CD8 T cells
Endogenous antigens (e.g. viral proteins)

MHC Class II (HLA-DR, DP, DQ in Humans; H2 I-A, I-E in mice)
Expressed on: professional APCs (DCs, macrophages, B cells)
Presents to: CD4 T cells
Exogenous antigens—endocytosed from outside

Cross Presentation via MHC Class I
Expressed on: professional APCs (DCs, macrophages, B cells)

Class II MHC presentation is the domain of professional APCs such as Dendritic Cells (DCs), macrophages, and B cells. What makes these cells special is their ability to express class II MHC molecules upon activation. Like MHC I molecules, MHC II molecules are synthesized in the ER. However, they are immediately bound to a chaperone protein called the invariant chain (Ii) which prevents loading of the newly synthesized class II molecules with low affinity peptides that may be found in the ER lumen. The class II MHC molecules are then delivered, with the help of Ii, to a specialized late endosomal compartment called the MHC class II Compartment (MIIC). Exogenous proteins destined for class II MHC presentation are taken in from the external milieu by endocytosis and are degraded by proteases in the endosomes. Endosomes containing high affinity class II peptides fuse to the MIIC where the peptides displace Ii from the class II molecule. The loaded class II MHC molecules are then transported to the cell surface via the late endosomal transport system.

The third means of antigen presentation also involves class I MHC molecules and is known as cross presentation. Cross presentation is defined as the presentation of exogenous antigens to CD8 T cells. Cross presentation appears to be restricted to certain types of dendritic cells (DCs).Cross presentation is important for CD8 T cell responses to virally infected cells, allogeneic cells, and tumor cells because CD8 T cells must also be activated by professional APCs in order to gain full effector function. The specialized DCs are able to capture internally synthesized antigens released from damaged or infected cells, internalize them, and present them to CD8 T cells on class I MHC molecules by mechanisms that are not well understood. Two different pathways have been proposed. One is similar to the canonical class I processing system in which the antigenic proteins gain access to the cytosol of the APC and are processed by proteasomes. The other involves endocytosis of the captured antigens and processing in endosomes similar to the class II pathway. In either case it’s not clear how the peptides are delivered to the class I MHC molecules and transported to the cell surface.

These three mechanisms of antigen presentation insure that professional APCs can initiate both Cd4 and Cd8 immune responses and that target cells such as virally infected cells, allogeneic cells, and tumor cells display the appropriate peptide MHC complexes for recognition by cytolytic CD8 T cells (CTLs).


Contributed by Steve Anderson, Ph.D.



Below is the current listing of Bethyl antibodies involved in antigen processing and presentation: