L

MHC-II:peptide

MHC-II:peptide

proteins

Figure 11-5. Stages in antigen processing and presentation to the surface of the cell by the MHC class I and II gene products. Redrawn after (Paul 1999) with permission. Original figure copyright Lippincott, Williams and Wilkins, 1999.

proteins

Figure 11-5. Stages in antigen processing and presentation to the surface of the cell by the MHC class I and II gene products. Redrawn after (Paul 1999) with permission. Original figure copyright Lippincott, Williams and Wilkins, 1999.

waste disposal. Class I genes are expressed on the surface of most somatic cells, whereas class II genes are expressed only on some types of immune cells, including B cells, activated T cells, macrophages, dendritic cells, and thymic epithelial cells (Klein and Sato 2000). In particular because most cells present an individual's class I molecules, the MHC has been viewed generically as a form of self/nonself recognition signaling.

Generally speaking, class I molecules carry endogenously derived peptides (intracellular, from viruses, for example) whereas class II molecules transport exoge-nously derived peptides (from extracellular self or foreign proteins such as bacteria or viruses that have not yet entered a cell), although this is not always true. Class I molecules plus antigen are recognized by killer T cells, whereas class II molecules and antigen are recognized by helper T cells (Klein and Sato 2000; Roitt, Brostoff et al. 1998). Thus an antigen presented by a class I molecule elicits a T cell killer response, whereas if the antigen is presented by a class II molecule, a helper T cell response follows.

Worn-out or misfolded proteins inside a cell are marked for degradation by a molecule called ubiquitin. The marked proteins are unfolded with the help of chap-erone molecules and fed to proteasomes, which fragment them. The resulting pep-tides are either degraded into amino acids, which float in the cytosol of the cell and are reused, or transferred into the endoplasmic reticulum (ER) for transfer to the cell surface. This is done by transporters associated with antigen processing, or TAPS. In the ER, class I molecules pick up these peptides for transport to the surface of the cell, where they are displayed.

Extracellular proteins are treated differently. They are surrounded by invaginations from the plasma membrane of a cell, which pinch off as endocytic vesicles and fuse with lysosomes to form endosomes. Class II molecules transport these peptides to the cell surface; they do not bind to peptides in the ER, but instead the class II molecules are enclosed in membranous vesicles that fuse with endosomes to form the MHC class II compartment where exogenous proteins are degraded and subsequently transported to the cell surface.

Degradation of endogenously derived proteins, including self proteins, happens all the time in most cells, and MHC class I molecules are constantly transporting peptides to the surface of cells. The action of class II molecules on exogenously derived proteins is less ubiquitous, however, generally restricted to cells that are specialized in phagocytosis or endocytosis. In any case, most cells are studded with MHC-peptide complexes all the time, hundreds of thousands of them, and the vast majority represent self peptides (Klein and Sato 2000).

Natural Killer Cells

A third kind of lymphocyte is the natural killer cell (NK). These cells originate in bone marrow. They do not express antigen receptors but have the ability to destroy some tumors by lysing tumor cells, and they play a role in innate immunity by killing cells infected with viruses.

Production of Immunoglobulin and T Cell Receptor Diversity

So much for the mechanics. To restate the evolutionary challenge presented to macroorganisms, pathogens have a much shorter life span and can rapidly out-evolve the ability of large organisms to defend against them. If recognition is the challenge, then immune systems are faced with ever- and unpredictably changing diversity. One strategy for keeping up is the generation of huge amounts of diversity in the adaptive immune systems of higher vertebrates. Although somewhat different in structure and function, the fundamental tools of this system, the TCR and immunoglobulins, are both produced by a very interesting somatic DNA recombination mechanism that is unusual because during the development of each lymphocyte lineage, the inherited genome in the antibody coding complexes of that cell is permanently altered. This mechanism has been traced to the emergence of the ancestral jawed vertebrate about 450 million years ago.

The immunoglobulin and TCR gene complexes contain sections of coding regions known as V (variable), D (diversity), and J (joining) elements, in which there are many duplicate coding elements (especially in the V region). Active recombination-

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