Regulation of the Expression of MHC Genes

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Just as with the expression of immunoglobulin genes (see above), the expression of MHC genes can also be modified by a variety of different factors. Several endogenous materials—most nota- bly some of the interferons and the tumor necrosis factor-α  (TNF-α),  previously discussed in Chapter 15—induce MHC class I gene expression in a variety of cell types (cf. David-Watine et al., 1990) including brain cells (Wong et al., 1984). Chemical inducers of differentiation such as sodium butyrate or hexamethylene bisacetamide may also amplify the expression of MHC class I antigens (Fenig et al., 1993).

Among the principal exogenous  factors regulating  the expression  of MHC antigens are viruses, both oncogenic and nononcogenic (cf. Maudsley and Pound, 1991). In the majority of instances, especially of oncogenic viruses, the effects are to downregulate the expression of both

Figure 19.16 Diagrams of the class I (left) and class II (right) molecules of the MHC showing the pep- tide-binding cleft and the subunit association thereof. (Adapted from Janeway and Travers, 1996, with per- mission of the authors and publisher.)

class I and class II MHC antigens. Some viruses, even including HIV, actually upregulate the expression of MHC class II antigens. The importance of this effect in the interaction of the host immune system with neoplastic cells is outlined later in this chapter.

Signaling Pathways and Lymphocyte Activation

As noted earlier, the interaction of T-helper and -suppressor lymphocytes with both T cells and B cells results in the secretion and release of a variety of factors, most of which are components of the cytokine system, some of whose members are indicated in Table 19.4. The table is not meant

to be exhaustive, since other cytokines—including other interleukins, hematopoietic factors, thy- mus hormones, and somatic growth factors—could  be included (Borecký, 1993). Most of the cytokines have specific receptors, and thus their interaction with such molecules on a cell sur- face can result in the initiation of signal pathways and alteration of gene expression involving a variety of genes including the MHC class I and II antigens, protein kinases, guanylate-binding proteins, and even tumor-associated antigens (Borecký, 1993).

Another major consequence of cytokine release and interaction with specific receptors is cell proliferation. Interleukin-2 or the T-cell growth factor is one of the major cytokines released during T-cell interactions involving MHC molecules and the T-cell receptor. As with other inter- actions of ligands with their receptors, a series of reactions is initiated involving signal transduc- tion mechanisms very similar to those described in Chapters 7 and 15. In Table 19.5 are listed the major events involved in T-lymphocyte activation from the time that cell-cell interaction oc- curs until proliferation of the T lymphocyte ensues. A similar sort of pathway is involved in the activation of B lymphocytes (DeFranco, 1993).

A diagram of signal transduction pathways in T lymphocytes may be seen in Figure 19.17. In the figure the function of the costimulatory protein, CD28, as well as the CD4/CD8 interac- tion is shown. Obviously,  all of these factors are involved in the signal transduction  pathway leading to the activation of transcription factors in the nucleus, altered gene expression, and ulti- mately cell proliferation. As noted above, the activation of T cells as well as that of D cells by mechanisms shown in Figure 19.17 and Table 19.5, leads to the production of various cytokines such as those listed in Table 19.4. Many of these cytokines, especially the interleukins and inter- ferons, interact with specific receptors on target cells such as other T cells and B cells to further stimulate gene transcription and cell replication. As indicated earlier with TNF-α  and TGF-β, signal transduction  pathways differ in their effector molecules.  In the case of interferons  and interleukins,  the signal transduction  pathway involves protein kinases termed JAKs as well as

Figure 19.17 Signal transduction  pathways in T lymphocytes.  Not all known interactions  with various costimulatory molecules and other cellular components are shown in the figure for simplicity. The principal events  involved  are ultimately  the activation  of transcription  factors  through  the MAP kinase  cascades (Chapter 7). As seen in this figure, the costimulatory  molecule CD28 signals via a protein tyrosine kinase (PTK) and phosphoinositide  kinase. Activation  of the T cell receptor (TCR) is also mediated through ty- rosine and MAP kinases. The CD4 or CD8 molecule is bound to the tyrosine kinase Lck, which phosphory- lates TCR enabling another tyrosine kinase, Zap-70, to bind to the T-cell receptor complex and become localized  to the membrane.  Zap-70  activates  phospholipase  C, resulting  in increased  diacylglycerol  and inositol 1,4,5-P3  levels. These latter changes result in a calcium-activated  pathway which together with the other pathways shown can activate the MAP kinase cascade. The different pathways are also indicated by the different shading of their components as noted. (Adapted from Hardy and Chaudhri, 1997, with permis- sion of the authors and publisher.)

STAT proteins which are phosphorylated,  bind to each other and translocate directly to the nu- cleus in a fashion somewhat similar to that of the Smads seen in signal transduction with TGF-β (Figure 16.8; Heim, 1999).

Effecting the Immune Response

As noted from Figure 19.12, the effective response of the humoral immune system involves ei- ther interaction of antibodies with cells or antigens, the antigen-antibody  complex being then effectively phagocytosed by appropriate scavenger cells such as macrophages in the instance of nonviable particles—or the reaction of the antibody with an antigen on the cell surface to which proteins of the complement system adhere—with subsequent formation of pores through the ac- tion of a component of complement, C9, also termed perforin (Lowin et al., 1992).

Cytotoxic T cells when interacting with target cells exhibiting the specific epitope to which they are sensitive and the presence of the MHC class I antigen result in a series of reactions de- picted in Figure 19.18, which include the formation of pores as with antigen-antibody-comple- ment reactions  noted above, as well as other mechanisms  involving  the direct induction  of apoptosis  by specific surface molecules.  In addition, cytolytic T cells on interaction  with the MHC-antigen epitope via the T-cell receptor produce granules filled with various lytic enzymes, which pass through the pores and further serve to cause apoptosis in the target cell (Figure 19.18).

For some years the exception to this mechanism was the NK cell which did not require MHC complex antigens for its action in causing apoptosis in target cells. NK cells do not ex- press the T-cell receptor on their surface, although they may express other surface molecules involved in the T-cell antigen receptor complex such as components of CD3 and the Fc receptor. Furthermore,  NK cells do not require expression of MHC class I molecules on the surface of their targets; rather, they are inhibited from killing cells expressing such molecules (see above). NK cells use a cytolytic machinery somewhat similar to that of specific cytolytic T cells (Figure 19.18),  especially  the perforin  pathway  (van  den Broek  et al., 1998).  Investigations  by Yokoyama (1995) do suggest that recognition of MHC class I molecules by NK cells may be involved in their cytolytic effects since the initial responses of NK cells to the target cell occur in the presence of MHC class I molecules on the target cell surface. It is likely that other mole- cules, some of which have yet to be defined, may allow the cytolytic effect of the NK cell to reach certain targets while protecting others.

Figure 19.18 Mechanisms of lymphocyte-mediated cytolysis. The figure is a schematic diagram of the nonsecretory receptor (left) and the secretory, perforin/granzyme-mediated (right) mechanisms of lympho- cytotoxicity. (After Berke, 1995, with permission of the author and publisher.)

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