group of genes that code for proteins found on the surfaces of cells that help the immune system recognize foreign substances. MHC proteins are found in all higher vertebrates. In human beings the complex is also called the human leukocyte antigen (HLA) system.

There are two major types of MHC protein molecules—class I and class II. Class I MHC molecules span the membrane of almost every cell in an organism, while class II molecules are restricted to cells of the immune system called macrophages and lymphocytes. In humans these molecules are encoded by several genes all clustered in the same region on chromosome 6. Each gene has an unusually large number of alleles (alternate forms of a gene that produce alternate forms of the protein). As a result, it is very rare for two individuals to have the same set of MHC molecules, which are collectively called a tissue type. The MHC also contains a variety of genes that code for other proteins—such as complement proteins, cytokines (chemical messengers), and enzymes—that are called class III MHC molecules.

MHC molecules are important components of the immune system because they allow T lymphocytes to detect cells, such as macrophages, that have injested infectious microorganisms. When a macrophage engulfs a microorganism, it partially digests it and displays peptide fragments of the microbe on its surface, bound to MHC molecules. The T lymphocyte recognizes the foreign fragment attached to the MHC molecule and binds to it, stimulating an immune response. In uninfected healthy cells, the MHC molecule presents peptides from its own cell (self peptides), to which T cells do not normally react.

MHC molecules were initially defined as antigens that stimulate an organism's immunologic response to transplanted organs (transplant) and tissues. In the 1950s skin graft experiments carried out in mice showed that graft rejection was an immune reaction mounted by the host organism against foreign tissue. The host recognized the MHC molecules on cells of the graft tissue as foreign antigens and attacked them. Thus, the main challenge in a successful transplantation is to find a host and a donor with tissue types as similar as possible. The term histocompatibility, derived from the Greek word histo (meaning “tissue”) and the English word compatibility, was applied to the MHC molecules to describe their function in transplantation reactions and does not reveal their true physiological function.