Components of the Immune System

The immune system comprtses several kinds ot lymphocytes as well as cells of the monocyte/macrophage lineage, dendritic cells, and NK cells. Lymphocytes, with their specific surface receptors, are the key to immunologic specificity Any given 1 or B lymphocyte possesses receptors with specificity for a particular epitope. When T or B lymphocytes bind antigen they respond by dividing to form an expanded clone of cells (clonal expansion) The B lymphocytes differentiate into plasma cells, which secrete specific antibody. The T lymphocytes secrete soluble factors known as lymphokines or interleukins, which are representatives of a large family of hormones, known generically as cytokines, that modulate the activities of other cells involved in the immune response. Some of the T and B cells revert to long-lived small lymphocytes responsible for immunologic metnoiy. Whereas antibodies and the receptors on B cells recognize epitopes on foreign antigens in their native conformation, T-cell receptors recognize short peptides in association with membrane glycoproteins known as MHC proteins.

Antigen-Presenting Cells

Cells of the dendritic cell and monocyte/macrophage lineages play a central role in the immune response to viruses, notably m antigen processing and presentation (Fig. 8-1). As a class, cells with these functions are called antigen-presenting cells (/IPC). The most efficient antigen-presenting cells are MHC class K-rich dendritic cells, including Langerhans cells of the skin and the interdigitating dendritic cells of lymph nodes, so named because they inter-digitate with CD4 1 T cells to which they present antigen. Unlike dendritic cells, macrophages are phagocytic; they express some class II MHC protein while resting, but more following activation. After priming and activation, B lymphocytes also serve as antigen-presenting cells; they are important during the latter stages of the primary response and during the secondary response. To understand the intricacies of antigen processing and presentation one must lirst know something about the structure and intracellular trafficking of MHC proteins.

The ma;or histocompatibility complex (MHC) is a genetic locus encoding three MHC rlass I proteins and at least six MHC class II proteins, each of which occurs in one of many alternative allelic forms. Class I glycoproteins are found in the plasma membrane of most types of cells; class II glycoproteins are confined principally to antigen-presenting cells. At the distal tip of each class of MHC protein there is a groove, usually occupied by a short peptide (Fig. 8-2). Peptides recovered from class I molecules are usually 8 or 9 amino acids long; peptides binding to class II proteins range from 13 to 17 ammo acids. Specific amino acids lining the groove of any particular MHC protein limit and determine the particular range of peptides that can occupy

Antiviral effect

Antibody ■ Virus neutralization

Complement-mediated lysis Antibody dependent cell-mediated cytotoxicity

Help lor B. Tc cells

Inllammalion

Immune cytolysis of Infected cells

Cytolysis of infected cells

Antibody- dependent cell-mediated cytotoxicity

Fig. 8-1 Cells involved in antiviral immune responses V, Virus or viral antigen, MHC I, MHC II, MHC proteins ot class I and fl, respectively, with viral peptide bound in gioove, Th, helpei, Td, delayed hypersensitivity, Tc, cytotoxic T lymphocytes; NK, natural killer cell, K, killer cell Antigen-presenting cells process virus or viral prolems via the endosomal pathway, and the peptides associate with class 11 MHC proteins. Some viral protein molecules produced during viral replication undergo pioteolysis and the resulting peptides associate with class 1 MHC proteins through the cytosolic pathway. (Modified from C A Mims and D O White "Viral Pathogenesis and tmmunology " Blackwell, Oxford, 1984 )

it. The peptide-MHC complex is in turn recognized, with a considerably higher degree of specificity, by the T-cell receptor (TCR) of the appropriate clone of T cells. During ontogeny, positive selection of developing T cells in the thymus by "self" MHC molecules results in mature T cells that can recognize foreign peptides only if they are in the groove of "self" MHC protein, not foreign MHC molecules. This phenomenon is known as MHC restriction.

Virus or viral proteins taken up by antigen-presenting cells pass progressively through early endosomes to late (acidic) endosomes and prelyso-somes, where they are degraded by proteolytic enzymes (the endosomal pathway). Certain of the resulting viral peptides are able to bind to newly synthesized class II MHC molecules which they encounter in these acidic endosomes on their way from the Golgi complex to the plasma membrane. In virus-infected cells, on the other hand, endogenously synthesized viral protein molecules are occasionally degraded in the cytosol, and the resulting peptides are translocated by special transporter molecules into the endoplasmic reticulum, where they assemble with class I MHC molecules to form a stable complex, which is then exported to the cell surface (the cytosolic pathway). Thus, in general, peptides derived from endogenously synthesized viral proteins in infected cells associate with MHC class I protein and the complex is recognized by CD8+ T cells, thus eliciting a Tc cell response, whereas peptides derived from exogenous viral proteins endocylosed by antigen-presenting cells associate with class II MHC protein and the complex is recognized by CD4'' T cells, leading to a Th cell response.

Although there is extensive polymorphism of MHC genes between people, any individual has only a limited number of different MHC proteins, and

Antigen presentation

Lymphocyte

MHC II + peptide

Infected cell

How To Bolster Your Immune System

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