Histocompatibility Molecules

Histocompatibility molecules are glycoproteins expressed at the surface of all vertebrate cells. They get their name because they are responsible for the compatibility - or rather the lack of it - of the tissues of genetically different individuals. Monozygotic ("identical") human twins have the same histocompatibility molecules on their cells, and they can accept transplants of tissue from each other. The rest of us have a set of histocompatibility molecules that is probably unique to us. A graft of our tissue into another human will provoke an immune response which, if left unchecked, will end in the rejection of the transplant. So the histocompatibility molecules of one individual act as antigens when introduced into a different individual. In fact, the histocompatibility molecules are often called histocompatibility antigens or transplantation antigens.

Class I Histocompatibility Molecules

• a transmembrane protein, called the heavy chain, most of which is exposed at the cell surface. The outermost domains contain two segments of alpha helix that form two ridges with a groove between them.
• a small molecule (e.g., a short peptide) attached noncovalently in the groove between the two alpha helices, rather like a hot dog in a bun
• a molecule of beta-2 microglobulin (ß₂m), which is also attached noncovalently (and thus is an example of an peripheral membrane protein).

Humans synthesize three different types of class I molecules designated HLA-A, HLA-B, and HLA-C. (HLA stands for human leukocyte antigen; because the molecules were first studied on leukocytes). These differ only in their heavy chain, all sharing the same type of beta-2 microglobulin. The genes encoding the different heavy chains are clustered on chromosome 6 in the major histocompatibility complex (MHC).

We inherit a gene for each of the three types of heavy chain from each parent so it is possible, in fact common, to express two allelic versions of each type. Thus a person heterozygous for HLA-A, HLA-B, and HLA-C expresses six different class I proteins. These are synthesized and displayed by most of the cells of the body (except those of the central nervous system).

Histocompatibility molecules present antigens to T cells

Although histocompatibility molecules were discovered because of the crucial role they play in graft rejection, clearly evolution did not give vertebrates these molecules for that function. So what is their normal function? The answer: to display antigens so that they can be "seen" by T lymphocytes. The antigen receptor on T lymphocytes (or T cells, as they are commonly called) "sees" an epitope that is a mosaic of the small molecule in the groove and portions of the alpha helices flanking it.

The small molecules ("hot dogs") are enormously diverse. They probably represent fragments derived from all the proteins present within the cell. These would include:

• fragments of normal cell constituents (These do not normally elicit an immune response.)
• fragments of molecules encoded by intracellular parasites (like viruses)
• fragments of proteins encoded by mutated genes in cancer cells

Class II Histocompatibility Molecules

Human class II molecules are designated HLA-D, and the genes encoding them are also located in the major histocompatibility complex (MHC). Class II molecules consist of two transmembrane polypeptides. These interact to form a groove at their outer end which, like class I molecules, always contains a fragment of antigen. But the fragments bound to class II molecules are derived from antigens that the cell has taken in from its surroundings. Extracellular molecules are engulfed by endocytosis. The endosomes fuse with lysosomes and their contents are partially digested. The resulting fragments are placed in class II molecules and returned to the cell surface.

Class II molecules, in contrast to class I, are normally expressed on only certain types of cells. These are cells like macrophages and B lymphocytes that specialize in processing and presenting extracellular antigens to T lymphocytes. Thus antigen presentation by class II molecules differs from that by class I in two important ways:

• all cells can present antigens with class I molecules, whereas only certain cells can do so with class II
• the antigen fragments (hot dogs) displayed in class I molecules are generated from macromolecules synthesized within the cell, whereas those displayed in class II molecules have been acquired from outside the cell.

Class I and class II molecules present antigen fragments to different subsets of T cells.

• The CD8 molecules on CD8⁺ T cells bind to a site found only on class I histocompatibility molecules (shown here as a gray hemisphere).
• The CD4 molecules on CD4⁺ T cells bind to a site found only on class II histocompatibility molecules (shown below as a yellow triangle).

The CD8⁺ T Cell/Class I Interaction

Because of the need for CD8 to bind to a receptor site found only on class I histocompatibility molecules, CD8⁺ T cells are only able to respond to antigens presented by class I molecules. Most CD8⁺ T cells are cytotoxic T cells (CTLs). They contain the machinery for destroying cells whose class I epitope they recognize.

Every time you get a viral infection, say influenza (flu), the virus invades certain cells of your body. Once inside, the virus subverts the metabolism of the cell to make more virus. This involves synthesizing molecules encoded by the viral genome. In due course, these are assembled into a fresh crop of virus particles that leave the cell (often killing it in the process) and spread to new cells.

Except while in transit from their old home to their new, the virus works inside cells safe from any antibodies. But early in their intracellular life, infected cells display fragments of the viral proteins being synthesized in the cytoplasm in their surface class I molecules.

Any cytotoxic T cells specific for that antigen will bind to the infected cell and often will be able to destroy it before it can release a fresh crop of virus.

The bottom line: the function of the body's CD8⁺ T cells is to monitor all the cells of the body ready to destroy any that express foreign antigen fragments in their class I molecules.

The CD4⁺ T Cell/Class II Interaction

• macrophages (phagocytic cells that develop from monocytes that have migrated from the blood to the tissues) and
• B lymphocytes ("B cells") that take up exogenous antigen by receptor-mediated endocytosis.

• have a T cell receptor (TCR) able to recognize a complex epitope comprising an antigenic fragment displayed by a class II molecule and
• bind a site on the class II molecule (shown above as a yellow triangle) with its CD4

• enter the cell cycle leading to the growth of a clone of identical T cells
• begin to secrete lymphokines

• activate other cells (e.g., more macrophages) to the region producing an inflammation (e.g., to cope with a bacterial infection
• activate B cells enabling them to develop into a clone of antibody-secreting cells. The CD4⁺ T cells that activate B cells are called Helper T cells.