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Major Histocompatibility Complex (MHC)
Both T and B cells use surface molecules to recognize antigen, they accomplish this in very different ways. In contrast to antibodies or B-cell receptors, which can recognize an antigen alone, T-cell receptors only recognize pieces of antigen that are positioned on the surface of other cells. These antigen pieces are held within the binding groove of a cell surface protein called the Major histocompatibility complex (MHC) molecule encoded by a cluster of genes collectively called the MHC locus. These fragments are generated inside the cell following antigen digestion, and the complex of the antigenic peptide plus MHC molecule then appears on the cell surface. MHC molecules thus act as a cell surface vessel for holding and displaying fragments of antigen so that approaching T cells can engage with this molecular complex via their T-cell receptors. The MHC in humans is known as human leukocyte antigens (HLA) complex.
In humans, the HLA complex of genes is located on short arm of chromosome 6 containing several genes that are critical to immune function. The HLA complex of genes is classified into three classes as follows:
- Class I: HLA-A, HLA-B, and HLA-C.
- Class II: HLA-DR, HLA-DQ, and HLA-DP. All of these are present within HLA-D region of HLA complex.
- Class III: Complement loci that encode for C2, C4, and factor B of complement system and TNFs alpha and beta.
Gene Products of HLA complex
- Class I MHC genes encode glycoproteins expressed on the surface of nearly all nucleated cells; the major function of the class I gene products is presentation of endogenous peptide antigens to CD8+ T cells.
- Class II MHC genes encode glycoproteins expressed predominantly on APCs (macrophages, dendritic cells, and B cells), where they primarily present exogenous antigenic peptides to CD4+ T cells.
- Class III MHC genes encode several different proteins, some with immune functions, including components of the complement system and molecules involved in inflammation.
Major Histocompatibility Complex Class I (MHC-I)
Class I molecules consist of a heavy polypeptide chain of 44 kDa non-covalently linked to a smaller 12 kDa peptide called β2-microglobulin. The largest part of the heavy chain is organized into three globular domains (α1, α2 and α3) which protrude from the cell surface; a hydrophobic section anchors the molecule in the membrane and a short hydrophilic sequence carries the C-terminus into the cytoplasm. The heavy chain has a variable and constant region. The variable region is highly pleomorphic. The polymorphism of these molecules is important in the recognition of self and non-self. The constant region of the heavy chain binds with the CD8 proteins of the cytotoxic T cells.
X-ray analysis of crystals of a human class I molecule shows both β2 -microglobulin and the α3 region resemble classic Ig domains in their folding pattern. The α1 and α2 domains interact to form a platform of eight antiparallel β strands spanned by two long α-helical regions. The structure forms a deep groove, or cleft with the long α helices as sides and the β strands of the β sheet as the bottom. This peptide-binding groove is located on the top surface of the class I MHC molecule, and bind a peptide of 8 to 10 amino acids.
Class I proteins are involved in graft rejection and cell-mediated cytolysis.
Major Histocompatibility Complex Class II (MHC-II)
Class II MHC molecules are also transmembrane glycoproteins, consisting of α and β polypeptide chains of molecular weight 33-kDa α chain and a 28-kDa β chain, which associate by noncovalent interactions. Class II molecule contains two external domains: α1 and α2 domains in one chain and β1 and β2domains in the other. There is considerable sequence homology with class I. Structural studies have shown that the α2 and β2 domains, the ones nearest to the cell membrane assume the characteristic Ig fold, while the α1 and β1 domains form the peptide-binding groove for processed antigen. The peptide-binding groove of class II molecules is composed of a floor of eight antiparallel β strands and sides of antiparallel α helices, where peptides typically ranging from 13 to 18 amino acids can bind.
Class II proteins are primarily responsible for the graft-versus-host response and the mixed leukocyte response.
Distribution of MHC
Essentially, all nucleated cells carry classical class I molecules. These are abundantly expressed on lymphoid cells, less so on liver, lung and kidney, and only sparsely on brain and skeletal muscle. In the human, the surface of the villous trophoblast lacks HLA-A and -B and bears HLA G, which does not appear on any other body cell. Class II molecules are also restricted in their expression, being present only on antigen presenting cells (APCs) such as B-cells, dendritic cells and macrophages and on thymic epithelium. When activated by agents such as interferon g, capillary endothelia and many epithelial cells in tissues other than the thymus, they can develop surface class II and increased expression of class I.
They function as cell surface markers enabling infected cells to signal cytotoxic and helper T-cells.
Importance of MHC
- Antibody molecules interact with antigen directly but the T-Cell Receptor (TCR) only recognizes antigen presented by MHC molecules on another cell, the Antigen Presenting Cell. The TCR is specific for antigen, but the antigen must be presented on a self-MHC molecule.
- The TCR is also specific for the MHC molecule. If the antigen is presented by another allelic form of the MHC molecule in vitro (usually in an experimental situation), there is no recognition by the TCR. This phenomenon is known as MHC restriction.
Peptide antigens associated with class I MHC molecules are recognized by CD8+ cytotoxic T lymphocytes, whereas class II-associated peptide antigens are recognized by CD4+ helper T cells.