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Expression of MHC Molecules

Because MHC molecules are required to present antigens to T lymphocytes, the expression of these proteins in a cell determines whether foreign (e.g., microbial) antigens in that cell will be recognized by T cells. There are several important features of the expression of MHC molecules that contribute to their role in protecting individuals from diverse microbial infections.

Class I molecules are constitutively expressed on virtually all nucleated cells, whereas class II molecules are expressed only on dendritic cells, B lymphocytes, macrophages, and a few other cell types. This pattern of MHC expression is linked to the functions of class I-restricted and class II-restricted T cells. The effector function of class I-restricted CD8+ CTLs is to kill cells infected with intracellular microbes, such as viruses, as well as tumors that express tumor antigens. The expression of class I MHC molecules on nucleated cells serves provides a display system for viral and tumor antigens. In contrast, class II-restricted CD4+ helper T lymphocytes have a set of functions that require recognizing antigen presented by a more limited number of cell types. In particular, naive CD4+ T cells need to recognize antigens that are captured and presented by dendritic cells in lymphoid organs. Differentiated CD4+ helper T lymphocytes function mainly to activate (or help) macrophages to eliminate extracellular microbes that have been phagocytosed and to activate B lymphocytes to make antibodies that also eliminate extracellular microbes. Class II molecules are expressed mainly on these cell types and provide a system for display of peptides derived from extracellular microbes and proteins.

Production of IFN-y

Resting APC (low MHC expression)

Cytokine-mediated class II MHC expression on APCs

Enhanced antigen presentation

Activated APC (high MHC expression)

Activated APC (high MHC expression)

Enhanced T cell response

FIGURE 6-9 Enhancement of class II MHC expression by IFN-y. IFN-y produced by NK cells and other cell types during innate immune reactions to microbes or by T cells during adaptive immune reactions, stimulates class II MHC expression on APCs and thus enhances the activation of CD4+ T cells. IFN-y and type I interferons have a similar effect on the expression of class I MHC molecules and the activation of CD8+ T cells.

The expression of MHC molecules is increased by cytokines produced during both innate and adaptive immune responses (Fig. 6-9). On most cell types, the interferons IFN-a, IFN-ß, and IFN-y increase the level of expression of class I molecules. The interferons are cytokines produced during the early innate immune response to many viruses (see Chapter 4). Thus, innate immune responses to viruses increase the expression of the MHC molecules that display viral antigens to virus-specific T cells. This is one of the mechanisms by which innate immunity stimulates adaptive immune responses.

The expression of class II molecules is also regulated by cytokines and other signals in different cells. IFN-y is the principal cytokine involved in stimulating expression of class II molecules in APCs such as dendritic cells and macrophages (see Fig. 6-9). IFN-y may be produced by NK cells during innate immune reactions and by antigen-activated T cells during adaptive immune reactions. The ability of IFN-y to increase class II MHC expression earlier than APCs is an amplification mechanism in adaptive immunity. As mentioned earlier, the expression of class II molecules also increases in response to signals from Toll-like receptors responding to microbial components, thus promoting the display of microbial antigens. B lymphocytes constitutively express class II molecules and can increase expression in response to antigen recognition and cytokines produced by helper T cells, thus enhancing antigen presentation to helper cells (see Chapter 11). IFN-y can also increase the expression of MHC molecules on vascular endothelial cells and other nonimmune cell types; the role of these cells in antigen presentation to T lymphocytes is unclear. Some cells, such as neurons, never appear to express class II molecules. Activated human but not mouse T cells express class II molecules after activation; however, no cytokine has been identified in this response, and its functional significance is unknown.

The rate of transcription is the major determinant of the level of MHC molecule synthesis and expression on the cell surface. Cytokines enhance MHC expression by stimulating the transcription of class I and class II genes in a wide variety of cell types. These effects are mediated by the binding of cytokine-activated transcription factors to DNA sequences in the promoter regions of MHC genes. Several transcription factors may be assembled and bind a protein called the class II transcription activator (CIITA), and the entire complex binds to the class II promoter and promotes efficient transcription. By keeping the complex of transcription factors together, CIITA functions as a master regulator of class II gene expression. CIITA is synthesized in response to IFN-y, explaining how this cytokine increases expression of class II MHC molecules. Mutations in several of these transcription factors have been identified as the cause of human immunodeficiency diseases associated with defective expression of MHC molecules. The best studied of these disorders is the bare lymphocyte syndrome (see Chapter 20). Knockout mice lacking CIITA also show reduced or absent class II expression on dendritic cells and B lymphocytes and an inability of IFN-y to induce class II on all cell types.

The expression of many of the proteins involved in antigen processing and presentation is coordinately regulated. For instance, IFN-y increases the transcription not only of class I and class II genes but also of several genes whose products are required for class I MHC assembly and peptide display, such as genes encoding the TAP transporter and some of the subunits of proteasomes, discussed later in the chapter.

MHC Molecules

Biochemical studies of MHC molecules culminated in the solution of the crystal structures for the extracellular portions of human class I and class II molecules. Subsequently, many MHC molecules with bound peptides have been crystallized and analyzed in detail. This knowledge has been enormously informative and, because of it, we now understand how MHC molecules display peptides. In this section, we first summarize the functionally important biochemical features that are common to class

TABLE 6-4 Features of Class I and Class II MHC Molecules

Feature

Class I MHC

Class II MHC

p2- Microglobulin (12 kD)

a and p

Locations of polymorphic residues

a1 and a2 domains

a1 and p1 domains

Binding site for T cell coreceptor

CD8 binds to a3 region

CD4 binds to p2 region

Size of peptide-binding cleft

Accommodates peptides of 8-11 residues

Accommodates peptides of 10-30 residues or more

Nomenclature Human Mouse

HLA-A, HLA-B, HLA-C H-2K, H-2D, H-2L

HLA-DR, HLA-DQ, HLA-DP I-A, I-E

I and class II MHC molecules. We then describe the structures of class I and class II proteins, pointing out their important similarities and differences (Table 6-4).

General Properties of MHC Molecules

All MHC molecules share certain structural characteristics that are critical for their role in peptide display and antigen recognition by T lymphocytes.

• Each MHC molecule consists of an extracellular peptide-binding cleft, or groove, followed by immunoglobulin (Ig)-like domains and transmembrane and cytoplasmic domains. Class I molecules are composed of one polypeptide chain encoded in the MHC and a second, non-MHC-encoded chain, whereas class II molecules are made up of two MHC-encoded polypeptide chains. Despite this difference, the overall three-dimensional structures of class I and class II molecules are similar.

• The polymorphic amino acid residues of MHC molecules are located in and adjacent to the peptide-binding cleft. This cleft is formed by the folding of the amino termini of the MHC-encoded proteins and is composed of paired a helices resting on a floor made up of an eight-stranded P-pleated sheet. The polymorphic residues, which are the amino acids that vary among different MHC alleles, are located in and around this cleft. This portion of the MHC molecule binds peptides for display to T cells, and the antigen receptors of T cells interact with the displayed peptide and with the a helices of the MHC molecules (see Fig. 6-1). Because of amino acid variability in this region, different MHC molecules bind and display different peptides and are recognized specifically by the antigen receptors of different T cells.

• The nonpolymorphic Ig-like domains of MHC molecules contain binding sites for the T cell molecules

CD4 and CD8. CD4 and CD8 are expressed on distinct subpopulations of mature T lymphocytes and participate, together with antigen receptors, in the recognition of antigen; that is, CD4 and CD8 are T cell "coreceptors" (see Chapter 7). CD4 binds selectively to class II MHC molecules, and CD8 binds to class I molecules. This is why CD4+ helper T cells recognize class II MHC molecules displaying peptides, whereas CD8+ T cells recognize class I MHC molecules with bound peptides. Stated differently, CD4+ T cells are class II

Class I MHC

FIGURE 6-10 Structure of a class I MHC molecule. The schematic diagram (left) illustrates the different regions of the MHC molecule (not drawn to scale). Class I molecules are composed of a polymorphic a chain noncovalently attached to the nonpolymorphic P2-microglobulin (P2m). The a chain is glycosylated; carbohydrate residues are not shown. The ribbon diagram (right) shows the structure of the extracellular portion of the HLA-B27 molecule with a bound peptide, resolved by x-ray crystallography. (Courtesy of Dr. P. Bjorkman, California Institute of Technology, Pasadena.)

FIGURE 6-10 Structure of a class I MHC molecule. The schematic diagram (left) illustrates the different regions of the MHC molecule (not drawn to scale). Class I molecules are composed of a polymorphic a chain noncovalently attached to the nonpolymorphic P2-microglobulin (P2m). The a chain is glycosylated; carbohydrate residues are not shown. The ribbon diagram (right) shows the structure of the extracellular portion of the HLA-B27 molecule with a bound peptide, resolved by x-ray crystallography. (Courtesy of Dr. P. Bjorkman, California Institute of Technology, Pasadena.)

MHC restricted, and CD8+ T cells are class I MHC restricted.

Class I MHC Molecules

Class I molecules consist of two noncovalently linked polypeptide chains, an MHC-encoded 44- to 47-kD a chain (or heavy chain) and a non-MHC-encoded 12-kD subunit called p2-microglobulin (Fig. 6-10). Each a chain is oriented so that about three quarters of the complete polypeptide extends into the extracellular milieu, a short hydrophobic segment spans the cell membrane, and the carboxyl-terminal residues are located in the cytoplasm. The amino-terminal (N-terminal) a1 and a2 segments of

HLA class I

Top view

HLA class II

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