Monocytes and Macrophages

Bone marrow–derived myeloid progenitor cells give rise to monocytes (mononuclear phagocytes of the reticuloendothelial system) that serve important immune functions. They constitute about 4% of the peripheral blood leukocytes and are morphologically identified by an abundant cytoplasm and a kidney-shaped nucleus. Their cytoplasm contains many enzymes, which are important for killing microorganisms and processing antigens. Monocytes differentiate into tissue-specific macrophages including Kupffer cells of the liver and brain microglia.

Natural Killer Cells

Natural killer cells make up about 2.5% of peripheral blood lymphocytes and are synonymous with large granular lymphocytes because of their large intracytoplasmic azurophilic granules and high cytoplasm-to-nucleus ratio. NK cells are activated primarily in response to interferons and are involved in the elimination of virally infected host cells; they also play a role in tumor immunity. Unlike cytotoxic CD8⁺ T cells, NK cells lack immunological memory and have the ability to kill a wide variety of tumor and virus-infected cells without MHC restriction (see the discussion of the function of MHC genes) or activation. NK cells lack the cell surface markers present on B cells and T cells. NK1.1⁺ T cells are a subset of cells sharing characteristics of both NK cells and T cells. These cells express the α/β TCR and the NK1.1 receptor and secrete large amounts of IFN-γ or interleukin 4 (IL-4) in response to TCR stimulation.

T Lymphocytes

T cells originate from the thymus. Differentiation of T cells occurs in the thymus, and every T cell that leaves the thymus is conferred with a unique specificity for recognizing antigens. T cells that recognize self-antigens are generally either deleted or rendered tolerant within the thymus, a process called central tolerance.

T cells may be divided into two groups on the basis of expression of either the CD4⁺ or CD8⁺ marker. Functionally, CD4⁺ T cells are involved in delayed-type hypersensitivity (DTH) responses and also provide help for B-cell differentiation (and hence are termed helper T cells). In contrast, CD8⁺ T cells are involved in class I restricted lysis of antigen-specific targets (and hence are termed cytotoxic T cells). T cells with suppressor or regulatory activity can express either CD4 or CD8.

T-Cell Receptors

The TCR consists of two glycosylated polypeptide chains, alpha (α) and beta (β), of 45,000 and 40,000 dalton molecular weight, respectively. This heterodimer of an α and β chain is linked by disulfide bonds. Amino acid sequences show that each chain consists of variable (V), joining (J), and constant (C) regions closely resembling Igs (Fig. 41.1). There are about 10² TCR-variable genes grouped by homology into a small number of families, compared with 10³ or greater for Igs (see later discussion). The principles governing generation of diversity in the TCR are very similar to those for Ig genes. T cells can only recognize short peptides that are associated with MHC molecules. In contrast, the Ig receptor can recognize peptides, whole proteins, nucleic acids, lipids, and small chemicals.

Fig. 41.1 Molecular and genetic organization of the T-cell receptor (TCR) and immunoglobulin (Ig) molecule. A-B, Structural organization of the TCR and Ig molecule. The TCR is a heterodimer consisting of two chains, a and b; the Ig molecule consists of two heavy and light chains. Both molecules are stabilized by interchain and intrachain disulfide bonds. Variable-region domains are located at the amino terminal, and constant-region domains are located on the carboxy terminal. The antigen-binding site on the Ig molecule is located between the variable-region domains of the heavy and light chains. The variable region of the TCR recognizes foreign peptides in the context of self-MHC (major histocompatibility complex) molecules. The TCR is also associated with the CD3 antigen (consisting of g, d, e, and z-z chains) to form the TCR complex. C, Organization of the gene families of Ig and TCR. The common feature of the four gene pools is that they contain a number of variable (V) gene segments that are separated from the constant (C) region genes by the joining (J) genes. In the case of the TCR b chain and the Ig heavy-chain gene, additional diversity (D) genes are present. During ontogeny, one of the V gene segments is juxtaposed to the J segment through a process of chromosomal rearrangement to form the V(D)J gene. This, along with the constant region genes, is transcribed to form messenger RNA and then protein.

T cells also express a variety of nonpolymorphic antigens on their surfaces. The most abundantly expressed is CD45, comprising 10% of lymphocyte membrane proteins. CD45 exists as a number of isoforms that differ in the molecular weight of their extracellular domains as a result of RNA splicing. These isoforms can be distinguished serologically. The low molecular weight (CD45RO) isoforms define activated, or memory, T-cell populations.

B Lymphocytes

B cells are the precursors of antibody-secreting cells. The cells develop in the bone marrow and during their ontogeny acquire Ig receptors that commit them to recognizing specific antigens for the rest of their lives. B cells normally express IgM on their cell surfaces but switch to other isotypes as a consequence of T-cell help, while maintaining antigen specificity (see later discussion). Following antigenic challenge, T lymphocytes assist (help) B cells directly (cognate interaction) or indirectly by secreting helper factors (noncognate interaction) to differentiate and form mature antibody-secreting plasma cells.

Immunoglobulins

Immunoglobulins are glycoproteins that are the secretory product of plasma cells. Their biochemical structure and genomic organization is shown in Fig. 41.1. All Ig molecules share a number of common features. Each molecule consists of two identical polypeptide light chains (kappa [κ] or lambda [λ]) linked to two identical heavy chains. The light and heavy chains are stabilized by intrachain and interchain disulfide bonds. According to the biochemical nature of the heavy chain, Igs are divided into five main classes: IgM, IgD, IgG, IgA, and IgE. These may be further divided into subclasses depending on differences in the heavy chain.

Each heavy and light chain consists of variable and constant regions. The amino terminus is characterized by sequence variability in both the light and the heavy chain, and each variable heavy- and light-chain unit acts as the antigen-binding site (the Fab portion). The carboxy terminal of the heavy chain (also known as the Fc portion) is involved in binding to host tissue and fixing complement. This part of the molecule is important for antibody-dependent, cell-mediated cytotoxicity by cells of the reticuloendothelial system and for complement-mediated cell lysis.

Classes of Igs differ in their ability to fix complement. In humans, IgM, IgG1, and IgG3 antibodies are capable of activating the complement cascade. Different Ig classes also differ in their transport properties and ability to bind to phagocytes. Fc binding to Fc receptors (FcR) present on macrophages, dendritic cells, neutrophils, NK cells, and B cells initiates signaling within the cell only when the receptors are cross-linked by immune complexes containing more than one IgG molecule. Different Fc receptors (FcR) mediate different cellular responses, some being predominantly stimulatory, while others are inhibitory.

Antigen Receptor Gene Rearrangements

During B- and T-cell development, multiple gene rearrangements occur to form their respective antigen receptors, the Ig and the TCR. Diversity of the antigen receptors is due to diversity in their principal components, the variable (V) gene segment and the joining (J) gene segments. One of the many V gene segments is juxtaposed by chromosomal rearrangements with one of the J segments (and when present, with the diversity [D] segment) to form the complete variable region gene. Recombinational inaccuracies at the joining sites of the V, D, and J regions further increase the diversity of the antigen receptors.

Constant (C) gene segments are present in all receptors. The V, D, J, and C gene segments along with the intervening noncoding gene segments between the J and C regions are initially transcribed into mature RNA. Through a process of RNA splicing, the noncoding gene segments are excised, and the V(D)JC messenger RNA (mRNA) is translated into protein. After binding antigen, B cells undergo somatic mutations that further increase the diversity and the affinity of antigen binding (affinity maturation). This phenomenon does not occur in T cells. During isotype switching in B cells, further rearrangements lead to recombination of the same variable region gene with new constant region genes (see Fig. 41.1).

Major Histocompatibility and Human Leukocyte Antigens

Major histocompatibility complex gene products or the human leukocyte antigens (HLAs) serve to distinguish self from nonself. In addition, they serve the important function of presenting antigen to the appropriate cells. The MHC class I gene product contains an MHC-encoded α chain, and a smaller non-MHC-encoded β₂-microglobulin chain. The MHC class II gene product consists of two polypeptide chains, α and β, which are noncovalently linked. Both class I and class II proteins are stabilized by intrachain disulfide bonds. Class I antigens are expressed on all nucleated cells, whereas class II antigens are constitutively expressed only on dendritic cells, macrophages, and B cells and are also expressed on a variety of activated cells including T cells, endothelial cells, and astrocytes.

In humans, class I molecules are HLA-A, B, and C, whereas the class II molecules are HLA-DP, DQ, and DR. Several alleles are recognized for each locus; thus the HLA-A locus has at least 20 alleles, and HLA-B has at least 40. The number of alleles for the D region appears to be as extensive as that for HLA-A, HLA-B, and HLA-C. In view of the extensive polymorphisms present, the chances of two unrelated individuals sharing identical HLA antigens are extremely low. The reason for the extensive diversity and evolutionary pressure that lead to this are not fully understood.

Class I antigens regulate the specificity of cytotoxic CD8⁺ T cells, which are responsible for killing cells bearing viral antigens or foreign transplantation antigens (Fig. 41.2). The target cells share class I MHC genes with the cytotoxic cell. Thus the cytotoxic cell that is specific for a particular virus is capable of recognizing the antigenic determinants of the virus only in association with a particular MHC class I gene product. The function of class II MHC gene products appears to be to regulate the specificity of T-helper cells, which in turn regulate DTH and antibody response to foreign antigens. Similarly, an immunized T-cell population will recognize a foreign antigen only if it is presented on the surface of an APC that shares the same class II MHC antigen specificity as the immunized T-cell population. Thus the functional specificity of the T-cell population is restricted by the MHC molecules they recognize. CD8⁺ T cells (cytotoxic) and CD4⁺ T cells (helper) are referred to as MHC class I and MHC class II restricted T cells, respectively (Fig. 41.3).

Fig. 41.2 The phenomenon of major histocompatibility complex (MHC) restriction. For antigen-specific cytolysis of virus-infected targets to occur, T cells should be sensitized to the virus and share the same class I human leukocyte antigen (HLA) with the target cell. In the lower part of the figure, the MHC class I antigen expressed on the CD8⁺ T cell is different from the MHC class 1 antigen expressed on the target cell; therefore lysis does not occur. TCR, T-cell receptor.

Fig. 41.3 Antigenic recognition of cytotoxic and helper T cells. The cytotoxic T cell recognizes viral peptides associated with human leukocyte antigen-A (HLA-A), HLA-B, or HLA-C molecules. The coreceptor for the helper T cell is the CD4 molecule. MHC, Major histocompatibility complex; TCR, T-cell receptor.

The analysis of the three-dimensional structure of the class I and class II molecules has confirmed the notion that these molecules are carriers of immunogenic peptides that are processed by APCs and presented on the cell surface (Fig. 41.4). Both MHC class I and class II molecules share similarities in crystal structure that allow them to accept and retain immunogenic peptides in grooves, or pockets, and present them to T cells.

Fig. 41.4 Schematic diagram of the human leukocyte antigen (HLA) complex in humans, located on chromosome 6. The HLA class I gene (HLA-A, -B, and -C) codes for a single heavy-chain molecule. The β₂-microglobulin is coded by genes on a different chromosome. The HLA class II genes (DR, DP, and DQ) form the αβ heterodimer. The HLA class III genes include those encoding for members of the complement family of proteins. MHC, Major histocompatibility complex.

Antigen Presentation

One of the crucial initial steps in the immune response is the presentation of encountered antigens to the immune system. Antigens are carried from their site of arrival in the periphery by way of lymphatics or blood vessels to the lymph nodes and spleen. There, antigens are then taken up by cells of the monocyte-macrophage lineage and by B cells, processed intracellularly, and presented not as whole molecules but as highly immunogenic peptides.

Accessory Molecules for T-Cell Activation

The interaction of MHC-peptide complex with T cells, although necessary, is insufficient for T-cell activation. Other classes of molecules are involved in T-cell antigen recognition, activation, intracellular signaling, adhesion, and trafficking of T cells to their target organs. The distinction between the functions of these classes of molecules is not absolute, and many may be involved in interactions between other cells of the immune system.

Costimulatory Molecules

Costimulatory molecules serve as a “second signal” to facilitate T-cell activation. Costimulatory pathways that are critical for T-cell activation include the B7-CD28 and CD40-CD154 pathways. Members of the integrin families including vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule (ICAM-1), and leukocyte function antigen 3 (LFA-3) can provide costimulatory signals, but they also play critical roles in T-cell adhesion, facilitate interaction with the APCs, mediate adhesion to nonhematopoietic cells such as endothelial cells, and guide cell traffic (Fig. 41.5).

Fig. 41.5 Antigen-driven activation of helper T cells. Proliferation of T cells requires the delivery of a number of concordant signals. Along with stimulation through the T-cell receptor–CD3 complex, the presence of appropriate costimulatory signals via CD28 antigen, adhesion molecules, leukocyte function antigen 1 (LFA1) and CD2, and the coreceptor molecule CD4 are essential for T-cell activation and proliferation. The membrane events of antigen recognition lead to activation of second messengers. The second messengers signal the nucleus and cell to divide and secrete cytokines. Interleukin 2 (IL-2) acts as an autocrine growth stimulator, thereby amplifying the response. ICAM, Intercellular adhesion molecule; IFN-γ, interferon γ; MHC, major histocompatibility complex; TCR, T-cell receptor; TNF, tumor necrosis factor.

The B7-CD28 interaction is one of the most extensively studied costimulatory systems. The B7 molecules are expressed on antigen-presenting cells, and their expression is induced in activated cells. There are two forms of B7, B7-1 (CD80) and B7-2 (CD86), that share some homology but have different expression kinetics. The B7 molecules interact with their ligand, CD28, which is constitutively expressed on most T cells. Binding of the CD28 molecule mediates intracytoplasmic signals that increase expression of the growth factor, IL-2, and enhance expression of the anti-apoptotic molecule, Bcl-x_L. An alternate ligand for B7 is CTLA-4, which is homologous to CD28 in structure, but in contrast to CD28, CTLA-4 functions to inhibit T-cell activation. Costimulatory molecules may deliver either a stimulatory (positive) or inhibitory (negative) signal for T-cell activation (Brunet et al., 1987). Examples of molecules delivering a positive costimulatory signal for T-cell activation include the B7-CD28, CD40-CD154 pathways. Examples of molecular pathways delivering a negative signal for T-cell activation include B7-CTLA4 and PD1-PD ligand (Khoury and Sayegh, 2004). The delicate balance between positive and negative regulatory signals can determine the outcome of a specific immune response.

Accessory Molecules for B-Cell Activation

Like T cells, B cells require accessory molecules that supplement signals mediated through cell-surface Igs. Signaling molecules whose functions are likely to be analogous to CD3 are linked to Ig. Unlike T cells that may only respond to peptide antigens, B cells can respond to proteins, peptides, polysaccharides, nucleic acids, lipids, and small chemicals. B cells responding to peptide antigens are dependent on T-cell help for proliferation and differentiation, and these antigens are termed thymus-dependent (T-dependent). Nonprotein antigens do not require T-cell help to induce antibody production and are therefore T-independent.

The interaction between B cells and T-helper (CD4⁺) cells requires expression of MHC class II by B cells and is antigen dependent. In addition, a number of other molecules mediate adhesion between T and B cells and induce signaling for B-cell activation. These include B7 expressed on B cells interacting with CD28 on T cells and CD40 on B cells interacting with CD154. Interaction of T-helper and B cells occurs in the peripheral lymphoid organs, initially in the primary follicles and later in the germinal centers of the follicle. Activation of B cells induces activation of transcription factors (c-Fos, JunB, NFκB, and c-Myc), which in turn promote proliferation and Ig secretion. Cytokines elicited from the T-helper cell induce isotype switching in B cells, producing stronger and long-lived memory responses, in contrast to weak IgM responses to T-independent antigens.

Further generation of high-affinity antibody-producing B cells and memory B cells occurs in the germinal center of lymphoid follicles through a process called affinity maturation. As the amount of available antigen lessens, B cells that do not express high-affinity receptors for antigen are eliminated by apoptosis. Some B cells lose the ability to produce Ig but survive for long periods and become memory B cells.

Cytokines

Cytokines play a major role in regulating the immune response. Cytokines are broadly divided into the following categories, which are not mutually exclusive: (1) growth factors: IL-1, IL-2, IL-3, and IL-4 and colony-stimulating factors; (2) activation factors, such as interferons (α, β, and γ, which are also antiviral); (3) regulatory or cytotoxic factors, including IL-10, IL-12, transforming growth factor beta (TGF-β), lymphotoxins, and tumor necrosis factor alpha (TNF-α); and (4) chemokines that are chemotactic inflammatory factors, such as IL-8, MIP-1α, and MIP-1β.

Cytokines are necessary for T-cell activation and for the amplification and modulation of the immune response. A limited representation of the cytokines that participate in the immune response is shown in Table 41.1. Secretion of IL-1 by macrophages results in stimulation of T cells. This leads to synthesis of IL-2 and IL-2 receptors and finally to the clonal expansion of T cells. Only activated T cells express the IL-2 receptor (CD25); therefore the cytokine-induced expansion favors antigen-activated cells only. T-cell activation causes secretion of interferon gamma (IFN-γ), which induces expression of MHC class I and class II molecules on many cell types including APCs. This in turn increases the T-cell response to the antigen. Secretion of IL-2 also results in activation of NK cells that mediate lysis of tumor cell targets. In addition, IL-3 is released, resulting in stimulation of hematopoietic stem cells. The signal for differentiation of B cells to form antibody-secreting cells involves clonal expansion and differentiation of virgin memory B cells. IL-4 and B-cell differentiation factors secreted by T cells induce differentiation and expansion of committed B cells to become plasma cells.

IFN-α and IFN-β are both type I interferons. IFN-α is produced by macrophages, whereas IFN-β is produced by fibroblasts. Both inhibit viral replication by causing cells to synthesize enzymes that interfere with viral replication. They also can inhibit the proliferation of lymphocytes by unknown mechanisms.

Although the emphasis has been on factors that cause expansion and differentiation of lymphocytes, there are cytokines that can down-regulate immune responses. Thus IFN-α and IFN-β, in addition to possessing antiviral properties, can modulate antibody response by virtue of their antiproliferative properties. Similarly, TGF-β (a cytokine produced by T cells and macrophages) can also decrease cell proliferation. IL-10, a growth factor for B cells, inhibits the production of IFN-γ and thus may have antiinflammatory effects.

CD4⁺ T-helper cells differentiate into T_H1 or T_H2 phenotypes, as well as a recently described T_H17 subset, which secrete characteristic cytokines and stimulate specific functions. T_H1 cells secrete IFN-γ, IL-2, and TNF-α. These cytokines exert proinflammatory functions and, in T_H1-mediated diseases such as MS, promote tissue injury. IL-2, TNF-α, and IFN-γ mediate activation of macrophages and induce DTH. T_H1 cell differentiation is driven by IL-12, a cytokine produced by monocytes and macrophages. In contrast, the T_H2 cytokines IL-4, IL-5, IL-6, IL-10, and IL-13 promote antibody production by B cells, enhance eosinophil functions, and generally suppress cell-mediated immunity (CMI). T_H3 cells secrete TGF-β, which inhibits proliferation of T cells and inhibits activation of macrophages. Cytokines of the T_H1 type may inhibit production of T_H2 cytokines and vice versa. More recently, a subset of T cells that predominantly produce IL-17 have been described (Yao et al., 1995). These cells are believed to represent a distinct subset from IFN-γ-producing T_H1 cells, evidenced by the dependence of T_HIL-17 cells on IL-6 and TGF-β for differentiation (Bettelli et al., 2006; Mangan et al., 2006; Veldhoen et al., 2006) and IL-23 for expansion (Aggarwal et al., 2003; Langrish et al., 2005), as opposed to T_H1 cells, which are dependent on IL-12 and IL-2, respectively, for differentiation and expansion. Both T_H1 and T_H2 cytokines have been shown to suppress the development of T_H17 cells (Harrington et al., 2005; Park et al., 2005). T_HIL-17 cells facilitate the recruitment of neutrophils and participate in the response to gram-negative organisms. These cells may also play a role in the initiation of autoimmune disease. Another effector T-cell subset, T_H9 cells, has recently been described (Dardalhon et al., 2008; Veldhoen et al., 2008). Driven by the combined effects of TGF-β and IL-4, T_H9 cells produce large amounts of IL-9 and IL-10. It has been shown that IL-9 combined with TGF-β can contribute to T_H17 cell differentiation, and T_H17 cells themselves can produce IL-9 (Elyaman et al., 2009).

Traditionally, T_H cell subsets have been distinguished by their patterns of cytokine production, but identification of distinguishing surface molecule markers has been a major advance in the field. Tim (T cell, immunoglobulin and mucin-domain containing molecules) represent an important family of molecules that encode cell-surface receptors involved in the regulation of T_H1 and T_H2 cell–mediated immunity. Tim-3 is specifically expressed on T_H1 cells and negatively regulates T_H1 responses through interaction with the Tim-3 ligand, galactin-9, also expressed on CD4⁺ T cells (Monney et al., 2002; Sabatos et al., 2003; Zhu et al., 2005). Tim-2 is expressed on T_H2 cells (Chakravarti et al., 2005), and appears to negatively regulate T_H2 cell proliferation, although this has not been fully established. Tim-1 is expressed on T_H2 cells > T_H1 cells, and interacts with Tim-4 on APCs to induce T-cell proliferation (Meyers et al., 2005).

Chemokines

Chemokines are a recently discovered and extensively studied group of molecules that aid in leukocyte mobility and directed movement. Chemokines may be grouped into two subfamilies based on the configuration and binding of the two terminal cysteine residues. If the two residues participating in disulfide bonding are adjacent, they are termed the C-C family (e.g., MCP, MIP-1α, RANTES). Those separated by one amino acid, are C-X-C family members (e.g., IL-8), where X indicates a nonconserved amino acid. An important recent discovery is that two chemokine receptors, CCR-5 and CXCR-4, can act as coreceptors for strains of HIV. Chemokines are produced by a variety of immune and nonimmune cells. Monocytes, T cells, basophils, and eosinophils express chemokine receptors, and these receptor-ligand interactions are critical to the recruitment of leukocytes into specific tissues.

B-Cell Inhibition

In most instances, an antigen is cleared either by cells of the reticuloendothelial system or through the formation of antigen-antibody complexes. These complexes can themselves result in the inhibition of B-cell differentiation and proliferation through binding of the Fc receptor to the CD32 (FcγRIIB) receptor on the surface of the B cell.

Immunoglobulin

The variable regions of the Ig and the TCR molecule represent novel proteins that can act as antigens. Antigenic variable regions are called idiotopes, and responses against such antigens are called anti-idiotypic. Niels Jerne’s network hypothesis postulates that anti-idiotypic responses serve to regulate the immune response; however, the extent to which this operates is unclear.

T Cells

Termination of the T-cell immune response is mediated by several mechanisms including anergy, deletion, and suppressor cell activity. Anergy or functional unresponsiveness occurs when there is insufficient T-cell activation. Repeated stimulation of T cells may lead to activation-induced cell death through apoptosis. Cytokine-mediated regulation can also serve to terminate the immune response, notably by secretion of T_H2 and T_H3 cytokines. Regulatory cells generally inhibit the immune response through secretion of cytokines, through cytotoxic mechanisms, or by modulation of the function of APCs. A combination of these mechanisms cooperate to maintain self-tolerance, particularly peripheral tolerance, and are discussed later.

Anergy Due to Failure of T-cell Activation

In normal circumstances, an APC presents antigen as a peptide + MHC complex (signal one). In the absence of signal one, the T cell dies because of neglect. If signal one is presented in the absence of costimulatory signals (signal two), the T cell becomes anergic. An example of this situation occurs when an antigen is presented by nonprofessional APCs that lack the appropriate costimulatory molecules (Fig. 41.6). However, when a T cell is activated, it up-regulates the expression of an alternate costimulatory molecule, CTLA-4. CTLA4 engagement by CD80 and CD86 on the surface of APCs sends a negative signal to the T cell, inhibiting cell growth and proliferation. Animals deficient for CTLA-4 expression on their T lymphocytes have an uncontrolled lymphoproliferative phenotype with autoreactivity (Waterhouse et al., 1995).

Fig. 41.6 A two-signal model of T-cell activation. Activation of the T-cell receptor (TCR) by an antigen major histocompatibility complex (MHC) provides signal 1, which is sufficient to induce the T cell to enter the cell cycle and begin blast transformation, which is characterized by an increase in cell size. Signal 2, the costimulatory signal, can be provided to the T cell through interaction of CD28 with molecules of the B7 family found on the surface of bone marrow–derived antigen-presenting cells (APCs). A, In this instance, TCR signals are complemented, enabling the T cell to proliferate, produce cytokines, and develop mature effector functions. B, In the absence of a second signal, T-cell activation is abortive, and the cell becomes anergic. Signal 2 might not be delivered if the APC does not express a costimulatory ligand on its surface, perhaps because a nonprofessional APC, such as an epithelial cell, is presenting antigen. IL, Interleukin.

Apoptosis

Apoptosis is the process in which a cell undergoes programmed cell death. As opposed to necrosis, when interruption of the supply of nutrients triggers cell death, apoptosis may be triggered by various signals including withdrawal of growth factors, cytokines, exposure to corticosteroids, and repeated exposure to antigens. Mediators of apoptosis include the Bcl family of genes, which are mostly antiapoptotic, and the Fas family of genes, which are proapoptotic. Activated T cells also express Fas ligand (CD95L or FasL) and Fas (CD95); ligation of Fas and FasL induces apoptosis of the T cells.