T-Lymphocyte Antigen Recognition and MHC Proteins

T-LYMPHOCYTE ANTIGEN RECOGNITION AND MHC PROTEINS

Epitopes for T-lymphocytes comprise exclusively linear peptide sequences. T-lymphocytes are unable to respond to carbohydrate, lipid or nucleic acid material and they only respond to peptide antigen when it is presented to the T-lymphocyte by surface proteins on the plasma membrane of host cells. These surface proteins are termed MHC proteins and can be subdivided into two main classes:

•   MHC class I proteins are expressed on the surface of all nucleated host cell membranes and present peptide antigen to cytotoxic T-lymphocytes.

•   MHC class II proteins are expressed only on a more specialized group of cells termed antigen-presenting cells (APCs), and present peptide antigen to helper T-lymphocytes.

Such a distinct cellular distribution of MHC proteins and restriction in presentation to discrete T-lymphocyte sub-populations may be remembered by considering the different T-lymphocyte functions. That is, all cells of the body have the potential to become infected with virus and undergo a cancerous change, and hence all cells must have the capacity to be destroyed by the actions of cytotoxic T-cells. As such, all cells of the body must possess MHC I molecules to afford antigen presentation to cytotoxic T-cells. In contrast, as a coordinator cell of the immune system, the helper T-cell must be able to respond to its environment in order to give appropriate signals or ‘help’ to other immune cells. Specialized APCs with the capacity to phagocytose interstitial proteinaceous material therefore undertake the function of ‘environmental sampling’. MHC class II proteins expressed on the surface of APCs will present peptide antigen to helper T-lymphocytes.

APCs include the macrophage tissue cell population, specialized APCs such as dendritic cells within the lymphatic system or Langerhans cells within the skin. B-lymphocytes also serve the function of an APC because they interact with protein antigen through high-affinity surface IgM molecules. Subsequently, they internalize the protein antigen for processing to generate peptides that will be presented by MHC II molecules expressed on the B-lymphocyte cell surface. Another cell type that can serve the function of an APC is the endothelial cell, which can be induced to express MHC II molecules by the action of the cytokine IFN-γ. It should not be overlooked that the APC can itself become infected with virus and undergo cancerous transformation, and therefore the APC, in addition to MHC II molecules, will also express the full complement of MHC I molecules on its surface. This process of MHC presentation of peptide and interaction with T-lymphocyte receptor is shown in Figure 9.8. A foreign peptide presented by a MHC molecule will be recognized by a TCR expressed on the surface of an appropriate T-lymphocyte. Once a particular TCR recognizes a peptide sequence as foreign, intracellular signals to activate the T-cell are sent via the CD3 complex present within the T-cell membrane. The recognition of peptide as foreign will lead to an immune response. Beyond antigen presentation, the interaction between MHC molecule and T-lymphocyte also serves to identify that the T-lymphocyte and host cell membrane arise from the same embryonic tissue. Tremendous interindividual differences, or more specifically polymorphisms, exist in the MHC proteins within a population. The T-lymphocyte undertakes this MHC surveillance through the possession of accessory molecules. Cytotoxic T-lymphocytes possess CD8+ molecules which interact with MHC I (Figure 9.8a), while helper T-lymphocytes possess CD4+ molecules which interact with MHC II (Figure 9.8b); hence the use of the terms CD8+ lymphocytes to refer to cytotoxic T-cells and CD4+ lymphocytes to refer to helper T-cells.