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The Molecular Perspective: Major Histocompatibility Complex

Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA

Correspondence: David S. Goodsell, Ph.D., Associate Professor, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu Website: http://www.scripps.edu/pub/goodsell

The human body is a dangerous place for viruses. When infecting a cell, viruses have to deal with our sticky antibodies, patrolling lymphocytes, and many other defenses. But once a virus gets comfortably inside a cell, it is insulated from these dangers by the cell membrane. But fortunately for us, our cells are not this hospitable. They have a powerful system to advertise all of the things going on inside, and when this includes a growing virus, they use this system to alert the immune system.

Our cells continually display small pieces of their own internal proteins, carrying them outside the cell membrane where the immune system can see them. Most of the time, these peptides are just pieces of the normal proteins found inside the cell. Each person’s immune system, early in life, is customized to ignore these peptides, so healthy cells are left alone to go about their business. However, if any of these peptides is unusual, it is recognized by the immune system, starting a series of events that will eventually lead to the death of the problematic cell.

The process starts inside the cell, where proteosomes break all different kinds of proteins into small peptides. These little peptides are transported into the endoplasmic reticulum where they are combined with the two subunits of the major histocompatibility complex (MHC) to form a nice stable complex. Then, the MHC is delivered to the surface of the cell, where it displays its peptide for several hours. The complex is designed so that it is only stable when the peptide is bound, which cleverly ensures that only peptides from inside the cell are displayed. If the peptide is lost once the complex reaches the surface, the whole thing falls apart before it can pick up random peptides from the surrounding environment.

The peptide is then recognized by T cell receptors on the surface of lymphocytes (Fig. 1). A series of coreceptors confirm the interaction and strengthen the link between the faulty cell and the lymphocyte. The cells are brought into close contact, and then large secretory granules are released into the narrow gap (Fig. 2). These granules include several noxious proteins, including perforin, which forms holes in the cell surface, and granzymes, which enter the cell and cut proteins inside. Some of these granzymes make strategic cuts in caspases inside the cell, triggering the process of apoptosis. The faulty cell then proceeds to destroy itself.

View larger version (50K): [in this window] [in a new window]   Figure 1. Display of foreign peptides by MHC. Our cells use two similar types of MHC for different purposes. MHC class I, shown on the left, is used my most of our cells to display their own peptides. In the illustration here, a peptide from the retrovirus HTLV (bright red) is bound to MHC (pink). A cytotoxic T cell recognizes the peptide with a T cell receptor (blue and purple), and strengthens the interaction with CD8 (green). This will initiate a cascade of signals in the cell, mobilizing the destructive machinery. MHC class II, shown at the right, plays a more specific role. In the illustration, a peptide from influenza virus (bright red) is bound to the MHC on the surface of a special antigen-presenting cell. This is recognized by T cell receptors (blue and purple) and CD4 (green) on a helper T cell. When this helper cell binds, it releases cytokines that strengthen the immune response. Atomic coordinates were taken from entries 1akj, 1bd2, 1fyt, 1jl4 and 1wio from the Protein Data Bank (http://www.pdb.org).

View larger version (164K): [in this window] [in a new window]   Figure 2. A cytotoxic T cell in action. The site of attack of a cytotoxic T cell against an infected cell is shown here in cross section. The infected cell, at the bottom, has displayed a foreign peptide in one of its MHC molecules (in orange). The cytotoxic T cell, at top, has responded by binding tightly to the infected cell and releasing a collection of cell-killing proteins (magenta) into the tight space in between. These include perforin, which forms pores in the cell surface, and granzymes, which enter the cell and digest key proteins inside.

It is becoming increasingly clear that MHC may also play a role in the natural control of cancer cells. Cancer cells contain many mutated proteins that may be displayed by MHC to alert the immune system. Tumor cells may also express normal proteins but in unusual places or in abnormal amounts, providing a potential signal to mobilize an immune response. The possibility of enhancing this response with vaccines is an exciting goal of current research.

ADDITIONAL READING

Russell JH, Ley TJ. Lymphocyte-mediated cytotoxicity. Annu Rev Immunol 2002;20:323–370.[CrossRef][Medline]

York IA, Rock KL. Antigen processing and presentation by the class I major histocompatibility complex. Annu Rev Immunol 1996;14:369–396.[CrossRef][Medline]

Boon T, Coulie PG, Van den Eynde B. Tumor antigens recognized by T cells. Immunol Today 1997;18:267–268.[Medline]

Received November 15, 2004; accepted for publication November 15, 2004.

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