T cells can only recognise antigens when they are displayed on cell surfaces. This is carried out by Antigen-presenting cells (APCs), the most important of which are dendritic cells, B cells and macrophages. APCs can digest proteins they encounter and display peptide fragments from them on their surfaces for another immune cell to recognise.
This process of antigen presentation allows T cells to “see” what proteins are present in the body and to form an adaptive immune response against them. In this article we shall discuss how antigens are processed, presented, and the recognised by T cells.
Antigens are delivered to the surface of APCs by Major Histocompatibility Complex (MHC) molecules. Different MHC molecules can bind different peptides. The MHC is highly polygenic and polymorphic which equips us to recognise a vast array of different antigens we might encounter. There are different classes of MHC, which have different functions:
- MHC class I molecules are found on all nucleated cells (not just professional APCs) and typically present intracellular antigens such as viruses.
- MHC class II molecules are only found on APCs and typically present extracellular antigens such as bacteria.
This is logical because should a virus be inside a cell of any type, the immune system needs to be able to respond to it. This also explains why pathogens inside human red blood cells (which are non-nucleated) can be difficult for the immune system to find, such as in malaria.
Whilst this is the general rule, in cross-presentation extracellular antigens can be presented by MHC class I and in autophagy intracellular antigens can be presented by MHC class II.
Before an antigen can be presented, it must first be processed. Processing transforms proteins into antigenic peptides.
MHC Class I Molecules
Intracellular peptides for MHC class I presentation are made by proteases and the proteasome in the cytosol, then transported into the endoplasmic reticulum via TAP (Transporter associated with Antigen Processing) to be further processed.
They are then assembled together with MHC I molecules and travel to the cell surface ready for presentation.
MCH Class II Molecules
The route of processing for exogenous antigens for MHC class II presentation begins with endocytosis of the antigen. Once inside the cell, they are encased within endosomes that acidify and activate proteases, to degrade the antigen.
MHC class II molecules are transported into endocytic vesicles where they bind peptide antigen, and then travel to the cell surface.
The antigen presented on MHCs is recognised by T cells using a T cell receptor (TCR). These are antigen-specific.
T Cell Receptors
Each T cell has thousands of TCRs, each with a unique specificity that collectively allows our immune system to recognise a wide array of antigens.
This diversity in TCRs is achieved through a process called V(D)J recombination during development in the thymus. TCR chains have a variable region where gene segments are randomly rearranged, using the proteins RAG1 and RAG2 to initiate cleavage and non-homologous end joining to rejoin the chains.
The diversity of the TCRs can be further increased by inserting or deleting nucleotides at the junctions of gene segments; together forming the potential to create up to 1015 unique TCRs.
TCRs are specific not only for a particular antigen but also for a specific MHC molecule. T cells will only recognise an antigen if a specific antigen with a specific MHC molecule is present: this phenomenon is called MHC restriction.
As well as the TCR, another T cell molecule is required for antigen recognition and is known as a co-receptor. These are either a CD4 or CD8 molecule:
- CD4 is present on T helper cells and only binds to antigen-MHC II complexes.
- CD8 is present on cytotoxic T cells and only binds to antigen-MHC I complexes.
This therefore leads to very different effects. Antigens presented with MHC II will activate T helper cells and antigens presented with MHC I activate cytotoxic T cells. Cytotoxic T cells will kill the cells that they recognise, whereas T helper cells have a broader range of effects on the presenting cell such as activation to produce antibodies (in the case of B cells) or activation of macrophages to kill their intracellular pathogens.
Clinical Relevance – Autoimmune disease
It is important to note that APCs may deliver foreign antigens or self-antigens. In the case of autoimmune diseases, self-antigens are presented to T cells, which then initiates an immune response against our own tissues.
For example, in Graves’ disease, TSHR (thyroid stimulating hormone receptor) acts as a self-antigen and is presented to T cells. This then activate B cells to produce autoantibodies against TSHRs in the thyroid. This results in activation of TSHRs leading to hyperthyroidism and a possible goitre.