Molecules that mark a cell as self are encoded by a group of genes that is contained in a sections of a specific chromosome known as the major histocompatibility complex (MHC). The prefix "histo" means tissue; the MHC was discovered in the course of tissue transplantation experiments. Because MHC genes and the molecules they encode vary widely in the details of their structure from one individual to another (a diversity known as polymorphism), transplants are very likely to be identified as foreign and rejected by the immune system.

Scientists eventually discovered a more natural role for the MHC: it is essential to the immune defenses. MHC markers determine which antigens an individual can respond to, and how strongly. Moreover, MHC markers allow immune cells such as B cells, T cells, and macrophages to recognize and communicate with one another.

One group of proteins encoded by the genes of the MHC are the markers of self that appear on almost all body cells. Known as class I MHC antigens, these molecules alert killer T cells to the presence of body cells that have been changed for the worse-infected with a virus or transformed by cancer-and that need to be eliminated.

A second group of MHC proteins, class II antigens, are found on B cells, macrophages, and other cells responsible for presenting foreign antigen to helper T cells. Class II products combine with particles of foreign antigen in a way that showcases the antigen and captures the attention of the helper T cell.

This focusing of T cell antigen recognition through class I and class II molecules is known as MHC (or histocompatibility) restriction.