Major Histocompatibility Complex (MHC)
These molecules play a very important role in the recognition of self and non-self antigens by T cells. The MHC consists of a cluster of >100 genes on chromosome 6 that encode a number of biologically important molecules (Fig. 1-9). These molecules are responsible for the rejection of tissue grafts by genetically disparate individuals, as the name histocompatibility indicates. These molecules present antigens to T lymphocytes; govern interactions between T cells, B cells and accessory cells; and control the intrathymic development of the TcR repertoire against foreign antigens (positive selection) and against self (negative selection) Human MHC protein products are called human leukocyte antigens (HLA).
The two most important HLA glycoproteins are designated as class I and class II molecules (Fig. 1-9).
MHC class I molecules are ubiquitous on somatic cells whereas MHC class II molecules are restricted to monocytes, macrophages, dendritic cells, B cells, Langerhans cells, keratinocytes, activated T cells and certain types of epithelial cells. MHC class I molecules have three extracellular domains (α1, α2 and β1), and a cytoplasmic tail. In contrast, MHC class II molecules have four extracellular domains (α1, α2, β1 and β2).
Three genes encode three independently expressed MHC class I molecules: HLA-A, -B and -C. Each gene contains three exons for the domains 1, 2 and 3. The MHC class II cluster, HLA-D, also contains three distinct genes, DP, DQ and DR, each of which has a separate set of exons for the α and β chain.
Three genes encode three independently expressed MHC class I molecules: HLA-A, -B and -C. Each gene contains three exons for the domains 1, 2 and 3. The MHC class II cluster, HLA-D, also contains three distinct genes, DP, DQ and DR, each of which has a separate set of exons for the α and β chain.
An important aspect of the HLA gene system is its polymorphism. Each gene, MHC class I (A, B and C) and MHC class II (DP, DQ and DR) exists in different forms, or alleles. HLA alleles are designated by numbers and subscripts. For example, two unrelated individuals may carry class I HLA-B, genes B5, and Bw41, respectively. Allelic gene products differ in one or more amino acids in the α and/or β domain(s). Large panels of specific antibodies are used to type HLA haplotypes of individuals using leukocytes that express class I and class II molecules. HLA typing is used for matching donors and recipients for organ/tissue transplantation and to predict the risk of certain diseases . In addition, the polymorphism of HLA genes has major implications for the function of class I and class II molecules (vide infra).
MHC molecules are required for antigen presentation to T cells (Fig. 1-12). Peptides associated with MHC class I and class II molecules are recognized by CD8+ and CD4+ T cells, respectively. Foreign protein antigens are taken up by various types of cells in the body, internalized and subjected to enzymatic degradation called antigen processing. Antigenic peptide fragments bind to MHC class II molecules and are then transported to the cell surface. This MHC/antigen complex is recognized by the TcR on CD4+ T cells. A CD4+ T cell activated by an appropriate class II/peptide antigen complex on an antigen-presenting cell, such as a B cell or macrophage, may become a helper cell for antibody or cell-mediated immune responses.
A different scenario is found for viral antigens in infected cells or tumor antigens. These antigens are processed to fragments, which are expressed in association with the class I molecule. The MHC class I/antigen complex is recognized via the TcR by CD8+ T lymphocytes, which become activated and differentiate into CTLs that destroy infected cells.
Variable domains of MHC class II molecules encoded by some allelic genes may be unable to bind a given antigenic peptide and thus fail to present the peptide to antigen-specific T cells. As a result, an immune response to this antigen cannot be mounted. Because of the association of high and low responses to a specific antigen with particular MHC class II alleles, MHC genes have been termed immune response genes. HLA typing reveals that individuals carrying certain alleles are at a higher risk of developing diseases such as ankylosing spondylitis, myasthenia gravis or type I diabetes mellitus. It is likely that this association reflects an underlying immunopathologic reaction involving MHC class I/II molecules or an association with other genes in the MHC.
MHC products control the selection of the immune repertoire of T lymphocytes. T cells interact with MHC class I/II molecules during their maturation in the thymus. This interaction kills immature cells whose TcR have a high affinity for self-MHC or for an MHC/self-protein complex by a mechanism called apoptosis or programmed cell death. Potentially autoreactive T cells would be eliminated in this fashion (negative selection). Furthermore, the selection process by MHC molecules determines the T cell repertoire of the individual against various foreign antigens (positive selection). This negative and positive sorting of T cells is called thymic selection.
Although, the presentation of antigen in the context of MHC molecules is essential for T cell recognition of peptide antigens, interactions between the MHC-bound peptide and TcR and the MHC class I or class II molecules, respectively, with CD8 or CD4 is not sufficient to activate T cells. Other ligands on antigen-presenting cells and their receptors on T cells are required to complete the process. These ligand-receptor interactions include the ligands ICAM-1, LFA-3, and B7-1/2 on antigen-presenting cells binding to their receptors LFA-1, CD2, and CD28/CTLA-4, respectively, on T cells (Fig. 1-19). These and other counterstructures for B7-1 and B7-2 appear to precisely control the extent of T cell activation. A different scenario is found for viral antigens in infected cells or tumor antigens. These antigens are processed to fragments, which are expressed in association with the class I molecule. The MHC class I/antigen complex is recognized via the TcR by CD8+ T lymphocytes, which become activated and differentiate into CTLs that destroy infected cells.
Variable domains of MHC class II molecules encoded by some allelic genes may be unable to bind a given antigenic peptide and thus fail to present the peptide to antigen-specific T cells. As a result, an immune response to this antigen cannot be mounted. Because of the association of high and low responses to a specific antigen with particular MHC class II alleles, MHC genes have been termed immune response genes. HLA typing reveals that individuals carrying certain alleles are at a higher risk of developing diseases such as ankylosing spondylitis, myasthenia gravis or type I diabetes mellitus. It is likely that this association reflects an underlying immunopathologic reaction involving MHC class I/II molecules or an association with other genes in the MHC.
MHC products control the selection of the immune repertoire of T lymphocytes. T cells interact with MHC class I/II molecules during their maturation in the thymus. This interaction kills immature cells whose TcR have a high affinity for self-MHC or for an MHC/self-protein complex by a mechanism called apoptosis or programmed cell death. Potentially autoreactive T cells would be eliminated in this fashion (negative selection). Furthermore, the selection process by MHC molecules determines the T cell repertoire of the individual against various foreign antigens (positive selection). This negative and positive sorting of T cells is called thymic selection.
