Major Histocompatibility Complex Molecules and Antigen Presentation to T Lymphocytes

PROPERTIES OF ANTIGENS RECOGNIZED BY T LYMPHOCYTES, 110

ANTIGEN CAPTURE AND THE FUNCTIONS OF ANTIGEN-PRESENTING CELLS, 111

Role of Dendritic Cells in Antigen Capture and Display, 112 Functions of Other Antigen-Presenting Cells, 117

THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC), 117

Discovery of the MHC, 117 MHC Genes, 118 MHC Molecules, 122

Binding of Peptides to MHC Molecules, 125 PROCESSING OF PROTEIN ANTIGENS, 127

The Class I MHC Pathway for Processing and Presentation of Cytosolic Proteins, 128

The Class II MHC Pathway for Processing and Presentation of Vesicular Proteins, 131 Cross-Presentation, 134

Physiologic Significance of MHC-Associated Antigen Presentation, 134

PRESENTATION OF NONPROTEIN ANTIGENS TO SUBSETS OF T CELLS, 136

SUMMARY, 136

The principal functions of T lymphocytes are to eradicate infections by intracellular microbes and to activate other cells, such as macrophages and B lymphocytes. To serve these functions, T cells have to overcome several challenges.

• There are very few naive T cells specific for any one antigen, and this small number has to be able to locate the foreign antigen, react against it, and eliminate it.

Solving this problem requires a specialized system for capturing antigen and bringing it to the organs where T cell responses can be initiated. The specialized cells that capture and display antigens and activate T lymphocytes are called antigen-presenting cells (APCs). Of these, dendritic cells are especially important for activating naive T cells, the critical event in initiating cell-mediated immune responses.

• Lymphocytes have to be able to combat pathogens at any site in the body regardless of where the pathogens enter. T cells find antigens from all regions of the body by visiting every secondary lymphoid organ in the body as a part of their recirculation (see Chapter 2). To facilitate immune responses, dendritic cells, which are present in all tissue sites, capture antigens and migrate to the same regions of lymphoid organs where recirculating T cells localize, thus maximizing the chance of T cells of a particular specificity finding the relevant antigen.

• The functions of some types of T lymphocytes require that they interact with other cells of the immune system, which may be dendritic cells, macrophages, and B lymphocytes. Other types of T lymphocytes must be able to interact with any infected host cell. To ensure that T cells interact only with other host cells but not directly with microbes, T cell antigen receptors are designed to see antigens displayed by host cell surface molecules and not antigens on microbes or antigens that are free in the circulation or extracellular fluids. This is in striking contrast to B lymphocytes, whose antigen receptors and secreted products, antibodies, can recognize antigens on microbial surfaces, and soluble antigens as well as cell-associated antigens. The task of displaying host cell-associated antigens for recognition by CD4+ and CD8+ T cells is performed by specialized proteins called major histocompatibility complex (MHC) molecules, which are expressed on the surfaces of host cells.

• Different T cells have to be able to respond to microbial antigens in different cellular compartments. For instance, defense against viruses in the circulation has to be mediated by antibodies, and the production of the most effective antibodies requires the participation of CD4+ helper T cells. But if the same virus infects a tissue cell, it becomes inaccessible to the antibody, and its eradication requires that CD8+ cytotoxic T lymphocytes (CTLs) kill the infected cells and eliminate the reservoir of infection. This separation of optimal responses occurs because APCs differentially handle antigens in different locations (extracellular and intra-cellular, respectively) and present these antigens to the different classes of T cells. The task of segregating antigens from various anatomic compartments and displaying them to different T cell populations is also performed by MHC molecules.

Thus, antigen capture and display to T cells is a specialized and finely orchestrated process with many important functional implications. Elucidation of the cell biology and molecular basis of this complex process has been a fascinating accomplishment, which encompasses fundamental biology as well as fine structural detail. In this chapter, we will describe how antigens are captured and displayed to T cells. In Chapter 7, we describe the antigen receptors of T cells, and in Chapters 9 and 10, we discuss the activation and effector functions of T lymphocytes.

TABLE 6-1 Features of Antigens Recognized by T Lymphocytes

Features of Antigens Recognized by T Cells

Explanation

Most T cells recognize peptides and no other molecules.

Only peptides bind to MHC molecules.

T cells recognize linear peptides and not conformational determinants of protein antigens.

Linear peptides bind to clefts of MHC molecules, and protein conformation is lost during the generation of these peptides.

T cells recognize cell-associated and not soluble antigens.

T cell receptors recognize only MHC-like shapes, and MHC molecules are membrane proteins that display stably bound peptides on cell surfaces.

CD4+ and CD8+ T cells preferentially recognize antigens sampled from the extracellular and cytosolic pools, respectively.

Pathways of assembly of MHC molecules ensure that class II molecules display peptides that are derived from extracellular proteins and taken up into vesicles in APCs and that class I molecules present peptides from cytosolic proteins; CD4 and CD8 bind to nonpolymorphic regions of class II and class I MHC molecules, respectively.

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