ACP medicine, 3rd Edition

Immunology/Allergy

Organs and Cells of the Immune System

John R. David M.D.1

Cox Terhorst Ph.D.2

1Richard Pearson Strong Professor, Department of Immunology and Infectious Diseases, Harvard School of Public Health, Professor of Medicine, Harvard Medical School

2Professor of Medicine, Harvard Medical School, Chief, Division of Immunology, Beth Israel Deaconess Medical Center

The authors have no commercial relationships with manufacturers of products or providers of services discussed in this subsection.

August 2003

The Characteristics of the Immune System

The immune system mediates the individual's relationship with the microbial environment. Immunity involves innate, or natural, responses and highly specific acquired, or adaptive, responses. The essential difference between the two types of immunity lies in the means by which microorganisms are recognized. In innate immunity, glycolipids and macromolecules with repeat patterns that are unique to infectious organisms are recognized by cell surface receptors on macrophages, dendritic cells, natural killer (NK) and NK T (NKT) cells, as well as by the complement system. In acquired immunity, lymphocytes use very specific antigen receptors to recognize infectious agents and other antigens, either directly or when processed by antigen-presenting cells (APCs), such as dendritic cells. Thus, an interplay exists between innate and acquired immunity at the level of the APC. Once an otherwise healthy person has had an infection with bacteria or with a virus, the immune system recognizes that pathogen and prevents its recurrence. In addition, the immune system has the remarkable capacity to discriminate between antigens, even if their structures are closely related. Lymphocytes can also react to self-antigens, causing autoimmunity.

The immune response needs to be able to distinguish between self and nonself. Otherwise, T cells and antibodies would constantly be attacking autologous cells, tissue components, or even commensal bacteria. In the 1950s, Sir Frank Macfarlane Burnet first proposed that in the prenatal state, the interaction of self-antigens with antigen-specific lymphocytes leads to the elimination of self-reactive lymphocytes and hence to immunologic tolerance.1 When immunologic tolerance breaks down, the antibodies and sensitized (antigen-reactive) cells that are directed against self-antigens cause autoimmune diseases [see 6:IX Immunologic Tolerance and Autoimmunity].

Lymphocytes

There are two major groups of lymphocytes, the T cells (also called thymus-derived lymphocytes, or T lymphocytes) and the B cells (also called bone marrow-derived lymphocytes, or B lymphocytes). T cells and B cells make up 80% to 95% of the peripheral blood lymphocytes.

T cells and B cells have a vast power of antigen recognition. Two unique features underlie this power: (1) a B cell family of variable genes, which combined can recognize an almost infinite number of antigens; and (2) a T cell family of variable genes with only a slightly more limited capacity. Neither T cells nor B cells constitute a homogeneous population of cells; each group comprises a number of subgroups that can be differentiated by the constant region of their receptors, by specific sets of developmentally expressed surface markers, by their location in lymphoid organs, and by their function. The binding of combinations of monoclonal antibodies to surface receptors is currently the most specific technique used to identify the major subsets of these cells.

T CELLS

Mature T cells express either αβ T cell receptors (TCR-αβ) or γδ TCR (TCR-γδ) in a complex with the CD3 proteins. CD4 is expressed on 50% to 65% of peripheral T αβ cells, and CD8 is expressed on 25% to 35% of peripheral T αβ cells. Usually, T γδ have no CD4 or CD8. Although CD4 and CD8 are expressed together on cortical thymocytes, only one or the other is expressed on the complementary subsets of mature thymocytes and peripheral T αβ cells (CD4+ and CD8+ T cells) [see Figure 1]. CD4+ T cells recognize antigen when the antigen is presented in association with major histocompatibility complex (MHC) class II molecules (HLA-D and HLA-DR) or in association with CD1d, the latter being NKT cells. CD8+ T cells recognize antigen in the context of MHC class I molecules (HLA-A, HLA-B, and HLA-C) [see 6:III Immune Response Mechanisms]. The context of antigen recognition by T γδ is unknown.

 

Figure 1. Lineages of Cells of the Immune System

Lineages of cells of the immune system and of blood cells all begin with the stem cell. Stem cells that differentiate to generate B cells reside in the bone marrow, and those that produce T cells migrate from the bone marrow to the thymus. T cell maturation involves the progressive expression of selected cell surface markers and the activation of various genes, including α, β, γ, and δ genes that code for the chains that make up the αβ and γδ T cell receptors (TCRs). Individuals lacking the Rag1 or Rag2 enzyme do not progress past the pre-T or pre-B cell stage and therefore have no lymphocytes. Positive and negative selection of T cells occurs at the so-called double-positive (CD4+,CD8+) stage. Natural killer cells develop both in the bone marrow and in the thymus.

CD4+ helper T (TH) cells can be further differentiated into TH1 and TH2 cells on the basis of the cytokines they produce.2 TH1 cells secrete interleukin-2 (IL-2) and interferon gamma (IFN-γ), which are important for cell-mediated immunity. TH2 cells secrete IL-4, IL-5, IL-6, IL-10, and IL-13, which are critical for antibody production. The cytokines that are produced by each of these cell types also influence the other cell type. For example, the IFN-γ produced by TH1 cells can inhibit the function of TH2 cells, whereas IL-10, which is secreted by TH2 cells, monocytes, macrophages, and B cells, can inhibit the function of TH1 cells. In addition to having a helper function, TH1 cells can induce inflammatory cascades leading to autoimmunity, as occurs in inflammatory bowel diseases and rheumatoid arthritis.

CD4 on the surface of helper T cells plays an important role in HIV infection. In early infection, the virus uses CD4 as a coreceptor, together with CCR5, which itself is a receptor for several chemokines, including RANTES (regulated on action, normal T cell expressed and secreted), macrophage inflammatory protein-1α (MIP-1α), and MIP-1β. One percent of whites are homozygous for a defect in the CCR5 receptor and are resistant to HIV infection. The chemokine receptor CCR4, which is a receptor for stromal cell-derived factor-1 (SDF-1), is involved in late HIV infection.3,4,5

B CELLS AND PLASMA CELLS

B cells are precursors of the immunoglobulin-producing cells (plasma cells) of the immune system and are identified by the presence of immunoglobulin on their surface. These surface membrane immunoglobulin-positive (SmIg+) cells constitute 5% to 15% of the peripheral blood lymphocytes. The majority of B cells have both IgM and IgD on their surface; about one quarter of all B cells have only IgM or IgD on their surface. One percent of B cells exhibit IgG or IgA.

On the surface of B cells is the complement receptor 2 (CR2 or CD21), which binds C3d/C3dg and Epstein-Barr virus. FcγRIIb (CD32) is the main Fc receptor on B cells, which is involved in B lymphocyte activation. A common marker that is used to identify B cells is CD19, which forms a larger complex with CD21 and CD81 (target for antiproliferative antigen-1 [TAPA-1]).6

B1 cells, a subset of B cells, develop early and have a very long life. B1 cell progenitors are found in fetal liver and in embryonic omentum but not in adult bone marrow. B1 cells that express CD5 on their surface are referred to as B1a, and B1 cells that lack CD5 are called B1b. B1 cells are frequently associated with autoantibody production. They also produce substantial amounts of IL-10.7

Under the influence of antigen, T cells, and accessory cells, B cells differentiate into plasma cells, the mature antibody-producing cells [seeFigure 1]. Plasma cells are larger than lymphocytes and are characterized by an eccentric round nucleus with coarse heterochromatin arranged in a cartwheel pattern. Plasma cells have a highly basophilic cytoplasm and a well-developed endoplasmic reticulum, often organized in parallel concentric layers. Plasma cells may be distended with granular material, which consists of the antibody they are producing [see Figure 2]. Sometimes, one or more of the endoplasmic cisterns are distended by large inclusions called Russell bodies. These bodies are aggregates of incompletely formed immunoglobulin molecules. Plasma cells no longer bear surface immunoglobulin. They are also end cells, which means they do not divide. The immature precursors of plasma cells, the plasmablasts, are difficult to distinguish from lymphoblasts and large lymphocytes. Plasma cells are not normally found in the peripheral blood.

 

Figure 2. Plasma Cells

Plasma cells are the antibody-producing cells of the immune system. They differentiate from B cells; are 6 to 20 µm in diameter; and have an eccentric nucleus, a highly basophilic cytoplasm, and a prominent, clear juxtanuclear area that contains the Golgi apparatus and the diplosome.

NATURAL KILLER CELLS

Natural killer cells are large granular lymphocytes that lack the TCR-CD3 complex characteristic of T cells or the SmIg characteristic of B cells. A bone marrow-derived stem cell is the precursor of T, B, and NK cells [see Figure 1]. In vitro, NK cells can kill a variety of tumor cells and virus-infected cells in a nonspecific manner; that is, they do not require previous sensitization or the presence of antibody to be cytotoxic. The granules contain pore-forming proteins that can mediate cell lysis. NK cells express killing inhibitory receptors (KIR) that recognize class 1 MHC molecules. Thus, NK cell functions are inhibited by cells that express MHC class 1 but are activated by cells lacking MHC class 1. Human NK cells express a second group of inhibitory receptors, which comprises two subunits: a variable subunit NKG and the invariant cell surface structure CD94. Its ligand is unknown. IL-12 stimulates NK cells to proliferate and to produce IFN-γ, which is important for a number of immune reactions.8,9

Monocytes, Macrophages, and Dendritic Cells

Monocytes belong to the mononuclear phagocytic system, previously called the reticuloendothelial system. They are large mononuclear cells that constitute 3% to 8% of the peripheral blood leukocytes. Their cytoplasm is much more abundant than that of the lymphocytes. Usually, their nucleus is eccentric and either oval or kidney shaped [see Figure 3]. Lysosomes filled with degradative enzymes appear as small vacuoles in the cytoplasm. Monocytes originate from promonocytes, which are rapidly dividing precursors in the bone marrow. When the mature cells enter the peripheral blood, they are called monocytes; when they leave the blood and infiltrate tissues, they undergo additional changes and are then known as macrophages. Other cells derived from this lineage include Kupffer cells, alveolar macrophages, microglia, and osteoclasts.

 

Figure 3. Monocyte

A monocyte (large cell at left), which can reach 17 µm in diameter, has abundant basophilic cytoplasm and a large eccentric nucleus.

Macrophages contain pattern recognition receptors (Toll-like receptors [TLRs] 1 through 10)10 and scavenger receptors. Furthermore, receptors for antibody and complement enhance their ability to phagocytose organisms that are coated with these substances. The antibody receptors recognize the Fc portion of IgG1, IgG3, and IgE. There are two complement receptors, CR1 and CR3. CR1 has a high affinity for the complement component C3b and a lower affinity for iC3b and C4b. CR3, also called macrophage antigen-1 (MAC-1), interacts with iC3b as well as with certain carbohydrate molecules, including carbohydrate-containing antigens of the protozoan Leishmania. Through these receptors, macrophages act as effector cells, attacking microorganisms and neoplastic cells and removing foreign material.

Of equal importance, macrophages present processed antigen to lymphocytes and thus play a major role in the induction of acquired immune responses. A small amount of MHC class II antigen is present on monocytes, and its expression is greatly increased when macrophages are activated. Macrophages can be activated by a number of cytokines, including IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage-activating factor (MAF), and migration inhibitory factor (MIF) [see 6:III Immune Response Mechanisms]. Cytokines such as IL-4 and transforming growth factor-β (TGF-β) antagonize this activation.

Macrophages themselves produce a large number of soluble substances that are important in the immune response and in the process of inflammation. These substances include enzymes such as plasminogen activating factor and elastase; growth factors such as GM-CSF; cytokines such as IL-1, IL-6, IL-10, IL-12, and tumor necrosis factor-α (TNF-α); factors that are critical for combating microorganisms, such as oxygen metabolites and nitric oxide; complement components for the classical and the alternative pathway; MIPs; and factors that promote tissue repair, such as fibroblast growth factor (FGF).

Dendritic cells are the professional APCs that engage specific responses by T cells.11,12,13 They are present where antigens and microorganisms have first contact with the body—for example, in the skin (Langerhans cells) and the gastrointestinal and respiratory tracts. The function of the dendritic cells is discussed [see Lymph Nodes and Spleen, below].

Lymphoid Organs and Lymphocyte Traffic

The immune system consists of a number of lymphoid organs, including the thymus, lymph nodes, spleen, and tonsils; aggregates of lymphoid tissue in nonlymphoid organs, such as Peyer patches in the gut; clusters of lymphoid cells dispersed throughout the connective and epithelial tissues of the body, as well as throughout the bone marrow and blood; and a variety of individual cells that travel from the various lymphoid organs to the rest of the body. The lymphocytes are derived from precursors in the bone marrow: the T cells develop in the thymus and are then exported to the periphery, whereas the B and NK cells develop in the bone marrow and then go out to the periphery. Of the nonlymphoid hematopoietic cells, the monocytes, macrophages, and dendritic cells are key elements of innate and acquired immunity, whereas granulocytes (e.g., neutrophils, eosinophils, basophils, and mast cells) and platelets play important accessory roles in the immune system.

THE THYMUS

The thymus, which originates from the third and fourth pharyngeal pouches of the embryo, lies in the anterior mediastinum and consists of many lobules, each containing a cortex and a medulla [see Figure 4]. Bone marrow-derived T cell precursors enter the thymus, congregating first in the subcapsular area. They develop into cells expressing the TCR-αβ-CD3 complex and subsequently acquire the potential to react with different peptides bound to MHC. These cortical CD4+,CD8+ thymocytes undergo either negative or positive selection, which involves complex mechanisms [see Development of the T Cell Repertoire, below]. Only a small percentage of positively selected thymocytes, CD4+(MCH class II recognizing) or CD8+ (MHC class 1 recognizing), migrate to the medulla and then move into the peripheral lymphoid system. It is unclear whether all γδ T cells differentiate in the thymus.

 

Figure 4. Schematic of the Thymus Gland

Many lobules make up the thymus gland. Most of the lymphocytes in the cortex are immature, rapidly dividing cells that can readily be destroyed by cortisone. During maturation, they move to the medulla, where they become immunocompetent and resistant to cortisone. From there, they migrate to the secondary lymphoid organs, including the lymph nodes and the spleen. Cell division and maturation are influenced by the epithelial cells; dense aggregates of these cells form bodies known as Hassall corpuscles.

Mature T cells emigrate through the wall of the postcapillary venules of the medulla to enter the bloodstream and subsequently home to the lymphoid system's peripheral organs. Once there, the lymphocytes leave the bloodstream, again through the postcapillary venules, and travel further into the T cell regions of the peripheral lymphoid organs. These include the inner cortex of the lymph nodes; the periarterial sheaths of the spleen; and the intranodular areas in Peyer patches, the tonsils, and the appendix. Some of the T cells in the intestinal mucosa (intraepithelial lymphocytes) are thought to differentiate outside the thymus.

Persons who are born without a thymus have lymphocytopenia, with a marked depletion or an absence of T cells. The T cell zones of the peripheral lymphoid system are also devoid of lymphocytes. There is marked impairment of cell-mediated immunity, and antibody responses that require cooperation from T cells (except the IgM response) are severely impaired [see 6:VIII Deficiencies in Immunoglobulins and Cell-Mediated Immunity]. The thymus involutes with age, which may explain the development of immune system deficiencies in elderly persons.

LYMPH NODES AND SPLEEN

The major sites of initial T cell activation are in the lymph nodes and in the spleen, where blood-borne lymphocytes and lymph-borne antigen, soluble mediators, and cells converge [see Figure 5]. Lymph and cells enter the node in the subcapsular region, through the afferent lymphatics; percolate into the subcapsular sinus; and leave through the efferent lymphatics in the hilum. In the spleen, the lymphocytes are concentrated in the white pulp, which consists of follicles with germinal centers that surround the central arterioles [seeFigure 6].

 

Figure 5. Schematic of Lymph Node

Lymph containing lymphocytes, antigen, and soluble mediators drains from surrounding tissues and enters the lymph nodes via afferent lymphatic vessels. The lymph node consists of a cortex and a medulla. The outermost area of the cortex has B cells organized into lymphoid follicles, and its deep, or paracortical, area consists mainly of T cells and dendritic cells. After B cells encounter antigens for which they have receptors, along with the appropriate T cells, central areas of marked B cell proliferation called germinal centers develop in the lymphoid follicles. As these reactions die out, the germinal centers become senescent. In the medulla are medullary cords, which are strings of macrophages and plasma cells.

 

Figure 6. Lymphoid Cell Circulation in the Spleen

In the spleen, the lymphoid cells around the splenic arteriole form the periarteriolar lymphoid sheath, which is predominantly a thymus-dependent area. The follicle with a germinal center contains B cells. The T cells are found mainly in the central region of the periarteriolar lymphoid sheaths, whereas the B cells in the germinal centers concentrate more toward the periphery of the sheaths. Lymphocytes enter and leave the periarteriolar lymphoid sheaths via the capillaries of the central arterioles in the marginal zone.

Lymph Nodes

The infrastructure of the lymph node is an extensive reticular network where APCs and T cells meet and interact. For example, bone marrow-derived dendritic cells in the skin pick up antigen and travel through the lymphatics to the draining lymph node. The cells then migrate through the floor of the subcapsular sinus of the lymph node to the interfollicular regions, where they settle in the reticular network of the paracortex as interdigitating dendritic cells (IDCs). T cells from the blood migrate through specialized postcapillary venules, known as high endothelial venules (HEVs), and migrate along the same reticular network, where they come in contact with the numerous antigen-presenting IDCs.14

The germinal centers contain B cells, which are derived from stem cells and differentiate in the bone marrow [see Figure 1]. The lymphoid follicles contain follicular dendritic cells (FDCs), which are not derived from the bone marrow. FDCs, which are found only in lymphoid follicles, express complement receptors CR1, CR2, CR3, and Fc receptors. These receptors enable the FDCs to present antigen to activated B cells in the form of antigen-antibody-complement complexes. FDCs can retain these complexes for a long time.

Active germinal centers are surrounded by a mantle of B cells (follicular mantle cells) that express IgD on their surface and can mature into plasma cells that produce IgM antibodies only. The B cells in the germinal center (centrocytes) undergo class switching to produce the other isotypes, such as IgG, IgA, and IgE. The B cells with high-affinity antibody on their surfaces are thought to be selected by binding to the antigen-retaining FDCs. The B cells that are not selected die by apoptosis (programmed cell death). The most mature B cell, the memory cell, is also found in the germinal center and can develop into plasma cells producing all the antibody isotypes.

Bone marrow-derived dendritic cells, found in the paracortical areas of the lymph node, are professional APCs that play a crucial role in initiating T cell-dependent immune responses.12,13,14 These cells are also found as immature cells in nonlymphoid organs, especially in the epidermis, where they are called Langerhans cells. Through their many receptors, particularly TLR1 through TLR10 and scavenger receptors, immature dendritic cells efficiently internalize and process antigens and present antigen through their MHC. There are two subsets of dendritic cells, myeloid and plasmacytoid, which produce distinct cytokines. Some cytokines (e.g., IL-1β and TNF-α), promote the migration of the dendritic cells via afferent lymphatics to the lymph nodes. At this location, they mature, lose their ability to phagocytose, and express critical costimulatory molecules CD80 (B7-1) and CD86 (B7-2); these costimulatory molecules enhance their ability to present antigen to T cells. Immature dendritic cells are also found in lymph nodes, where these cells can phagocytize antigen entering via the afferent lymphatics and then mature into APCs.

MUCOSAL AND SKIN IMMUNE RESPONSES

Lymphocytes are also found in various other locations. Gut-associated lymphoid tissue includes Peyer patches and the appendix. These gut-associated lymphoid tissues contain regions with concentrations of T cells or B cells similar to those found in germinal centers. Specialized epithelial cells termed M cells are thought to have a unique ability to take up and present antigen to the adjacent lymphocytes.15 M cells are found close to Peyer patches. Other lymphocytes in the intestine are the lamina propria lymphocytes (LPLs), found in the villi, and the intraepithelial lymphocytes (IELs), found between epithelial cells. Migration and adherence of LPLs are in part dictated by integrins and selectins, which are surface molecules on tissues and cells that mediate cell interactions and homing. Mucosa-associated lymphoid cells are also found in the respiratory tract and genitourinary tract. The specialized immune system of the skin contains Langerhans cells in the epidermis (specialized myeloid dendritic cells) and a higher concentration of γδ T cells than elsewhere.16

LYMPHOCYTE CIRCULATION

There are three major types of lymphocyte circulation: (1) the seeding of the stem cells from the fetal liver or bone marrow to the primary lymphoid organs and the subsequent differentiation and distribution of these cells to the peripheral lymphoid system, (2) the recirculation of lymphocytes from blood to lymph to blood, and (3) the distribution of effector cells to particular parts of the body. Lymphocytes circulate continuously from blood to tissues and back to the blood. However, the trafficking of naive T cells (CD45RA) is different from that of activated effector or memory cells (CD45RO). Naive T cells recirculate through the secondary lymphoid tissues, such as the lymph nodes, spleen, tonsils, and Peyer patches, to special microenvironments where they encounter antigen, cytokines, and other cells leading to their activation. In contrast, activated effector or memory cells can also traffic to extralymphoid sites in various tissues, such as skin and intestinal lamina propria.17

The homing of lymphocytes to the vascular endothelium and their passage through it are controlled by the expression of various receptors on the lymphocyte surface and counterreceptors on the vascular endothelium. To stop the flow of cells in the blood and lymph vessels, initial primary adhesion occurs between lymphocyte receptors on the cells' microvilli, such as L-selectin, and the counterreceptor on the endothelium, such as peripheral lymph node addressin (PNAd). Other cell receptors allow attachment to endothelial E-selectin and P-selectin. Subsequently, the cells can attach and roll using integrin-Ig surface receptors such as α4β7 and α4β1, which bind to endothelial mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and vascular cell adhesion molecule-1 (VCAM-1), respectively. These interactions can lead to stable arrest involving a receptor that triggers adhesion through intracellular signaling by a guanosine triphosphate (GTP) binding protein. Cooperation between receptor interactions is essential because the initial interaction with L-selectin may be too weak to induce the LFA-1/ICAM-1 (leukocyte-function-associated antigen-1/intercellular adhesion molecule-1) stable interaction and therefore requires the α4β7/MAdCAM-1 interaction. In contrast, when tissues display high levels of receptor L-selectin, contact and rolling mediated by L-selectin may be sufficient to allow LFA-1-mediated stable arrest. The lymphocytes can then pass through the vascular endothelium, a process called diapedesis. A similar process is involved with the diapedesis of other leukocytes.17

Variations on these mechanisms are thought to channel subsets of lymphocytes to the various microenvironments in the lymph nodes, such as the germinal centers, the paracortical areas, and the T zone, where cells, antigen, and soluble factors lead to particular immunologic responses. These microenvironments are further regulated by various cytokines, such as TGF-β1, which can upregulate integrins and mediate B cell binding to APCs. Cytokines such as TNF-α regulate lymphocyte adhesion receptors, and other cytokines influence lymphocyte activity as they traverse the tissues. Some chemokines, such as RANTES, also activate the expression of adhesion molecules on the surface of effector T cells. Other chemokines, such as thymus-expressed chemokine (TECK), recruit T cells bearing the TECK receptors (CCR9) to their homing organ, in this case the gut.18,19

The Hallmarks of the Immune System: Specificity and Memory

The immune responses are controlled by three large gene families: (1) the genes coding for the variable elements of the immunoglobulins, (2) the genes coding for the TCRs, and (3) the genes coding for the MHC antigens [see 6:II Antigens, Antibodies, and T Cell Receptors]. In each person, there are an enormous number of genes coding for the variable elements of the immunoglobulins and TCRs, allowing specific recognition of millions of antigens. However, the extreme variability of the MHC applies to the population as a whole; any individual will have only a few variations.

The ability of T cells and antibodies produced by B cells to discriminate between antigens is governed by two independent sets of variable region genes for T and B cells, each composed of rearranging V (variable), D (diversity), and J (joining) DNA segments. Rearrangement of the DNA sequences of these genes occurs as T cells and B cells mature, giving rise to TCRs and immunoglobulins. Additional somatic mutation occurs in B cells during further maturation, which expands the repertoire. This system can discriminate between billions of antigens [see 6:II Antigens, Antibodies, and T Cell Receptors].

Each lymphocyte has a surface receptor that recognizes a single antigenic determinant, or epitope. B cell receptors recognize native antigens. After B cells interact with an antigen, they proliferate and differentiate into plasma cells for the production of antibodies, and some become memory cells.

Before being recognized by T cells, an antigen is taken up by an APC (e.g., a dendritic cell or a macrophage), which breaks up the antigen into small peptide fragments. In the APC, certain peptide fragments or epitopes are taken up by MHC class II molecules and carried to the surface of the APC. Thus, TCRs do not recognize native antigen, only processed parts of it [see 6:II Antigens, Antibodies, and T Cell Receptors].

The requirement that the antigen be presented in association with an MHC class I or II molecule is referred to as MHC restriction. The nature of the MHC explains why some individuals may not respond to certain antigens. For example, although TCRs recognize epitopes that are bound to MHC molecules, some antigen peptides may not fit into the groove of the particular MHC molecule of an individual. Thus, the appropriate T cell type will not react to that epitope, and the individual will not be able to mount an immune response against it.

DEVELOPMENT OF THE T CELL REPERTOIRE

Of the two types of T cells, αβ and γδ, only the development of the cells that express TCR-αβ is well understood. After gene rearrangement occurs, the TCR-αβ is expressed on the surface of the immature cortical thymocyte together with the CD3 proteins [see Figure 1]. At about the same time as gene rearrangement occurs, CD4, CD8, and CD2 are expressed.6 Single-positive (either CD4+ or CD8+) mature thymocytes bearing high levels of TCR-αβ are selected from the pool of CD4+,CD8+ thymocytes by processes termed positive selection and negative selection.

Positive Selection

Positive selection is controlled by epithelial cells of the thymic cortex and dedicated APCs, such as macrophages, dendritic cells, and interdigitating cells. Many of these stromal cells are located in the corticomedullary junction. Because T cells can react to antigens only in association with self-MHC, only T cells with a TCR that can bind to self-MHC are selected. When these cells react with self-MHC on thymic stromal cells, CD4+,CD8+ TCR-αβ cells that bind to MHC class II molecules become CD4+ and CD8-, downregulating the CD8 and upregulating the TCR-CD3 complex. Conversely, the CD4+,CD8+ cells that bind to MHC class I molecules downregulate the CD4 and become CD4-,CD8+ TCR-αβ cells. In this manner, self-MHC-restricted CD4+ TCR-αβ cells and CD8+ TCR-αβ cells are selected. Only thymocytes whose TCR has a moderate affinity for MHC-peptide are positively selected. CD4 or CD8 cells contribute to the avidity of the interaction as they themselves bind to MHC class II and class I, respectively.

Negative Selection

Most T cells do not interact with self-MHC and therefore undergo apoptosis because of the lack of any interaction. The active process of negative selection eliminates T cells that have a TCR with a high avidity for MHC-peptide. If they were not removed, such T cells could cause serious autoimmune disease. There are many self-antigens on thymic epithelial cells, and studies show that certain self-antigens can be presented by various APCs in the thymus, such as macrophages and dendritic cells. It is possible that negative selection for some self-antigens occurs when the T cells move to the peripheral lymphoid system after leaving the thymus. This high-affinity interaction between the self-antigen presented by the MHC and the TCR on immature T cells triggers several processes leading to cell death (e.g., apoptosis) (see below).

POSITIVE AND NEGATIVE SELECTION OF B CELLS

Positive selection of precursor B cells takes place in the bone marrow. The pre-B cells bear on their surface the IgM heavy chain (µ) in association with the so-called surrogate light chain (lambda 5 or λ5). If the latter receptor is not on the surface, the cell is eliminated by apoptosis. Pre-B cells develop into immature B cells, which carry IgM on their surface. Those cells develop into mature B cells unless they are eliminated by antigen recognition and negative selection in the lymph nodes. If the affinity is high, elimination involves apoptosis, whereas if the affinity is low, it involves anergy (the cell is present but does not develop).

APOPTOSIS

Removal of autoreactive T and B cells in the periphery also uses apoptosis. Apoptotic signals acting on the cell membrane lead to programmed cell death with nuclear chromatin condensation and cleaving, and within minutes to hours, the cell is destroyed and cleared by macrophages. The main receptors on lymphoid cells that trigger apoptosis are members of the 18-member family of TNF receptors.20Examples include the Fas receptor (CD95/APO-1), which is triggered by Fas ligand; and the TNF receptor-1 (TNFR-1), triggered by TNF-α and lymphotoxin-α. Of note, the TNFRs also trigger pathways that lead to activation of nuclear factor κB (NF-κB), which protects against apoptosis.21 The signals for apoptosis eventually act on a family of cysteine proteases similar to the IL-1b converting enzyme (ICE), the prototype that acts on the cytokine precursor IL-1b, converting it to the active cytokine. ICE-related proteases activate other proteases, which then act on a number of substrates; this, in turn, leads to apoptosis.

AMPLIFICATION AND THE AMNESTIC RESPONSE

Characteristic of the immune response is its ability to increase the number of antigen-specific lymphocytes after an antigenic stimulus occurs; because of memory T and B cells, subsequent exposure to the same antigen results in a faster and a greater response (i.e., the anamnestic response). The basis for this enhanced response is the proliferation of antigen-specific lymphocytes and the production of memory cells after lymphocytes interact with an antigen. These responses are mediated through production of cytokines by lymphocytes and other cells [see 6:III Immune Response Mechanisms]. Immune response mechanisms are also amplified through the release of mediator substances from antibody-coated mast cells and basophils, the activation of complement proteins, and the expression of integrin molecules on cells. Altered vascular permeability, the expression of receptors for leukocytes on endothelial cells, and the release of chemotactic factors through these secondary mechanisms attract a host of other cell types to the reaction. These cells greatly contribute to the resulting inflammation by aiding the phagocytic process and the disposal of foreign antigens.

After T cells interact with an antigen, they proliferate and differentiate into effector cells, some helper T cells, and other cytotoxic T cells (CTLs); all of these have a memory cell component. An independent lineage of CD4+ T cells are regulatory T cells (Treg), which control immune responses by producing inhibitory cytokines and by direct cell-to-cell contact.22,23 Antigen-specific Treg cells may also develop as an independent lineage in the thymus.24 The memory aspects of Treg cells are not known.

The memory B cells enhance the immune response to previously encountered antigen as part of the anamnestic response. These memory B cells undergo somatic mutation in the variable regions of their immunoglobulin genes. When this somatic mutation occurs in the lymph node germinal centers that contain antigens bound to follicular dendritic cells, it leads to the selection of memory B cells that have high-affinity receptors for the antigens.

Acknowledgments

Figures 1, 4, and 5 Seward Hung.

Figure 6 Carol Donner.

References

  1. Burnet M: The Clonal Selection Theory of Acquired Immunity. Cambridge University Press, London, 1959
  2. Mosmann TR, Coffman RL: Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol 46:111, 1989
  3. Feng Y, Broder CC, Kennedy PE, et al: HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272:872, 1996
  4. Choe H, Farzan M, Sun Y, et al: The β-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85:1135, 1996
  5. Doranz BJ, Rucker J, Yi Y, et al: A dual-tropic primary HIV-1 isolate that uses fusin and the β-chemokine receptors CKR-5, CKR-3, and CKR-2 as fusion cofactors. Cell 85:1149, 1996
  6. CD Index. PROW (Protein Reviews on the Web). National Center for Biotechnology Information. 2002http://www.ncbi.nlm.nih.gov/prow/guide/45277084.htm
  7. Qin XF, Schwers S, Yu W, et al: Secondary V(D)J recombination in B-1 cells. Nature 397:355, 1999
  8. Natarajan K, Dimasi N, Wang J, et al: Structure and function of natural killer cell receptors: multiple molecular solutions to self, nonself discrimination. Annu Rev Immunol 20:853, 2002
  9. Vilches C, Parham P: KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol 20:217, 2002
  10. Janeway CA Jr, Medzhitov R: Innate immune recognition. Annu Rev Immunol 20:197, 2002
  11. Mellman I, Steinman RM: Dendritic cells: specialized and regulated antigen processing machines. Cell 106:255, 2001
  12. Rissoan MC, Soumelis V, Kadowaki N, et al: Reciprocal control of T helper cell and dendritic cell differentiation. Science 283:1183, 1999
  13. Siegal FP, Kadowaki N, Shodell M, et al: The nature of the principal type 1 interferon-producing cells in human blood. Science 284:1835, 1999
  14. Liu YJ, Kanzler H, Soumelis V, et al: Dendritic cell lineage, plasticity and cross-regulation. Nat Immunol 2:585, 2001
  15. Neutra MR, Mantis NJ, Kraehenbuhl JP: Collaboration of epithelial cells with organized mucosal lymphoid tissues. Nat Immunol 2:1004, 2001
  16. Randolph GJ: Is maturation required for Langerhans cell migration? J Exp Med 196:413, 2002
  17. Steeber DA, Tedder TF: Adhesion molecule cascades direct lymphocyte recirculation and leukocyte migration during inflammation. Immunol Res 22:299, 2000
  18. Rossi D, Zlotnik A: The biology of chemokines and their receptors. Annu Rev Immunol 18:217, 2002
  19. Sallusto F, Mackay CR, Lanzavecchia A: The role of chemokine receptors in primary, effector, and memory immune responses. Annu Rev Immunol 18:593, 2000
  20. Gupta S: A decision between life and death during TNF-alpha-induced signaling. J Clin Immunol 22:185, 2002
  21. Beg AA, Baltimore D: An essential role for NF-κB in preventing TNF-α-induced cell death. Science 274:782, 1996
  22. Shimizu J, Yamazaki S, Takahashi T, et al: Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3:135, 2002
  23. Sakaguchi S: Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101:455, 2000
  24. Jordan MS, Boesteanu A, Reed AJ, et al: Thymic selection of CD4+CD25+regulatory T cells induced by an agonist self-peptide. Nat Immunol 2:301, 2001

Editors: Dale, David C.; Federman, Daniel D.