628 Nature Vol. 297 24 June 1982 A beginner's guide to major histocompatibility complex function from Polly Matzinger and Rose Zamoyska TuE glycoproteins encoded by the major 'MHC restriction' of T-cell recognition. complex on the surface of the presenting histocompatibility complex (MHC) are Nearly all tissues express Class cell: or, alternatively, that a complex does guides by which cells of the immune system molecules and, if infected, can be form, but for various reasons there are no distinguish both each other from all other destroyed by active T killer cells. However, helper T cells able to recognize it. tissues, and also all cells of the body from in many species, Class I molecules are not How do MHC molecules activate T cells? non-cells (such as bacteria, viruses, toxins, expressed by mature red blood cells (having There are at least two possible ways in etc.). These two different modes of no DNA, red cells cannot support virus which MHC proteins could act as T-ccll discrimination require two different sets of replication) nor by sperm (although they activators. MHC-coded cell surface molecules, Class I are foreign invaders, sperm are usually I. Like hormones, they might work and Class II. welcome). directly, activating any T cell which binds Class I molecules are characteristic of cells Class II molecules are characteristic of cells them. An example of the importance of the of the immune system 2. The binding of MHC molecules by T recognition of cells versus non-cellular While T killer cells cope with cell-bound cells may trigger the antigen-presenting cell material can be seen in the immune virus, antibodies secreted by activated 'B' to send activation signals to the bound T response to a virus infection, which is celJ.s deal with free virus particles. In order cell. T cells binding virus alone would fought mainly by a subset ofT lymphocytes to be activated, resting B cells require therefore not trigger the antigen-presenting called T killer cells. This set of lethally signals from a subset of T cells called (not cell and would not receive the activation destructive lymphocytes can kill virus surprisingly) T helper cells. If a T helper cell signal. The fact that both Class 1 and Class infected cells before synthesis of new specific for virus is to help a B cell make II molecules are transmembrane proteins, viruses is complete, thus preventing the antibody against the virus, it must have the and the observation that not every cell spread of the infection. But how do T killer capacity to recognize not only the virus but expressing these molecules can act as T-cell cells distinguish between virus infected also the B cell. It would be futile for T inducers, support the latter possibility. cells, which they can destroy, and free virus helper cells to send signals to cells outside Further evidence that MHC molecules act as particles, which they are powerless to stop? the immune system (a virally infected liver presenting cell triggers comes from The T cell population consists of cell, for example) so, unlike T killer cells, T transplantation experiments. millions of constantly circulating lym­ helper cells do not recognize virus in the MHC genes, being highly polymorphic, phocytes, each one bearing receptors able context of the ubiquitously expressed Class are the major barriers to tissue trans­ to bind to one particular three-dimensional I molecules. Instead they are limited to the plantation. T cells distinguish between the structure. This results in a heterogeneous recognition of virus in the context of Class products of self and foreign MHC alleles population which can recognize a wide II molecules, which are expressed mainly with great precision, destroying any tissue variety of foreign molecules. Normally by B cells and antigen-presenting cells. The bearing foreign MHC products. The mag­ these T cells are quiescent and must be activation of T helper cells may be nitude of this reaction is greatly reduced if activated to become effective killer cells. described in a similar way to the MHC­ the foreign tissue is first cleared of its Their activation is not a simple process but restricted activation of T killer cells. resident presenting cells, even though the requires the participation of a special Circulating T helper cells encounter virus host's presenting cells should be able to accessory cell called the "antigen­ structures on the surface of a presenting pick up the foreign MHC molecules and presenting cell". A virus entering the body cell. They are activated as a result of activate T cells against them. Thus there is is picked up by the presenting cells which interacting with virus and Class II clearly a difference between a foreign process it and present it to the roving T cell molecules on the presenting surfaces, and MHC molecule in its original presenting population. Those few T cells which have will subsequently assist virus-specific B cell membrane and the same molecule receptors specific for viral structure will cells carrying the same Class II molecules. when it is picked up and displayed by the bind to the presenting cell. Although there Class II genes were originally discovered host's presenting cell. Perhaps the rep­ may be resting T cells which can bind to as immune response (IR) genes, so called resented foreign MHC is no longer virus alone, these are not activated. Only because animals which carried different appropriateiy linked up inside the cell to act those T cells which recognize both the Class MHC alleles differed in their ability to as a triggering device. It would then be I cell surface molecules and the viral make immune responses to certain foreign treated like any other foreign molecule, structures on the presenting cell are molecules. This now appears to be ex­ activating only those T cells which induced to proliferate and differentiate plained by the 'guidance' function of the recognize it in association with the host's into active killer cells. Since induced T cells MHC molecules. It is known that a foreign own MHC proteins. Since the grafted maintain their specificity, and since only molecule may be recognized more tissue does not express these host MHC those T cells which bind both viruses and efficiently with one Class II allele than with molecules, it would not be recognized by Class I cell surface molecules are induced, another. Animals bearing class II alleles the activated T cells and would not be the resulting activated killer cells are that are poorly recognized in association rejected. committed to the recognition of cell-bound with the foreign molecule will not generate What is it about their structure that virus. Furthermore, activated killer cells activated T helper cells and will allows MHC molecules to associate with so are extremely precise in their recognition of consequently be unable to produce strong many foreign molecules? How is their both virus and MHC molecules, dis­ antibody responses. It has been suggested structure related to their ability to act as criminating between closely related strains that an MHC molecule might be inefficient triggering devices? Are T cells evolu­ of virus and also distinguishing between at presenting a particular antigen because tionarily pre-programmed to look at them different Class I alleles. An animal bearing the two molecules do not form a good or are the specific T cells selected from a a particular Class I allele 'a', for example, randomly generated population of resting will produce killer cells which lyse infected cells? How many different MHC molecules target cells expressing 'a' but will ignore are there? With the molecules and their infected target cells bearing 'b' alleles. This Polly Matzinger and Rose Zamoyska are in the genes in hand (see the following article) we obligate recognition of foreign molecules Department of Pathology, University of may soon have the answers to these in the context of MHC proteins is called Cambridge. questions. lJ 0028-0836/ 82/250628-0 1$01 .00 e:>1982 Macmillan Journals Ltd .