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The immune system consists of cellular and molecular components that work together to destroy antigens (Ags).
Antigen-Presenting Cells
Although some Ags can stimulate the immune response directly, T cell–dependent acquired immune responses typically require antigen-presenting cells (APCs) to present Ag-derived peptides within major histocompatibility complex (MHC) molecules. Intracellular Ag (eg, viruses) can be processed and presented to CD8 cytotoxic T cells by any nucleated cell because all nucleated cells express class I MHC molecules. However, extracellular Ag must be processed into peptides and complexed with surface class II MHC molecules on professional APCs to be recognized by CD4 helper T (TH) cells. The following cells constitutively express class II MHC molecules and therefore act as professional APCs:
Monocytes in the circulation are precursors to tissue macrophages. Monocytes migrate into tissues, where over about 8 h, they develop into macrophages under the influence of macrophage colony-stimulating factor (M-CSF), secreted by various cell types (eg, endothelial cells, fibroblasts). At infection sites, activated T cells secrete cytokines (eg, interferon-γ [IFN-γ]) that induce production of macrophage migration inhibitory factor, preventing macrophages from leaving.
Macrophages are activated by IFN-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF). Activated macrophages kill intracellular organisms and secrete IL-1 and tumor necrosis factor-α (TNF-α). These cytokines potentiate the secretion of IFN-γ and GM-CSF and increase the expression of adhesion molecules on endothelial cells, facilitating leukocyte influx and destruction of pathogens.
Dendritic cells are present in the skin (as Langerhans' cells), lymph nodes, and tissues throughout the body. Dendritic cells in the skin act as sentinel APCs, taking up Ag, then travel to local lymph nodes where they can activate T cells. Follicular dendritic cells are a distinct lineage, do not express class II MHC molecules, and therefore do not present Ag to TH cells. However, they have receptors for the crystallizable fragment (Fc) region of IgG and for complement, which enable them to bind with immune complexes and present the complex to B cells in germinal centers of secondary lymphoid organs.
Polymorphonuclear Leukocytes
Polymorphonuclear (PMN) leukocytes, also called granulocytes because their cytoplasm contains granules, include
All, except for mast cells, occur in the circulation, and all have multilobed nuclei. Mast cells are tissue-based and functionally similar to circulating blood basophils.
Neutrophils constitute 40 to 70% of total WBCs; they are a first line of defense against infection. Mature neutrophils have a half-life of about 2 to 3 days. During acute inflammatory responses (eg, to infection), neutrophils, drawn by chemotactic factors and alerted by the expression of adhesion molecules on blood vessel endothelium, leave the circulation and enter tissues. Their purpose is to phagocytose and digest pathogens. Microorganisms are killed when phagocytosis generates lytic enzymes and reactive O2 compounds (eg, superoxide, hypochlorous acid) and triggers release of granule contents (eg, defensins, proteases, bactericidal permeability-increasing protein, lactoferrin, and lysozymes). DNA and histones are also released, and they, with granule contents such as elastase, generate fibers in the surrounding tissues; the fibers may facilitate killing by trapping bacteria and focusing enzyme activity.
Eosinophils constitute up to 5% of WBCs. They target organisms too large to be engulfed; they kill by secreting toxic substances (eg, reactive O2 compounds similar to those produced in neutrophils), major basic protein (which is toxic to parasites), eosinophil cationic protein, and several enzymes. Eosinophils are also a major source of inflammatory mediators (eg, prostaglandins, leukotrienes, platelet-activating factor, many cytokines).
Basophils constitute < 5% of WBCs and share several characteristics with mast cells, although the 2 cell types have distinct lineages. Both have high-affinity receptors for IgE called FcεRI. When these cells encounter certain Ags, the bivalent IgE molecules bound to the receptors become cross-linked, triggering cell degranulation with release of preformed inflammatory mediators (eg, histamine, platelet-activating factor) and generation of newly synthesized mediators (eg, leukotrienes, prostaglandins, thromboxanes).
Mast cells occur in different tissues of the body. Mucosal mast cell granules contain tryptase and chondroitin sulfate; connective tissue mast cell granules contain tryptase, chymase, and heparin. By releasing these mediators, mast cells play a key role in generating protective acute inflammatory responses; basophils and mast cells are the source of type I hypersensitivity reactions associated with atopic allergy (see Allergic and Other Hypersensitivity Disorders: Atopic and Allergic Disorders). Degranulation can be triggered by cross-linking of IgE receptors or by the anaphylatoxin complement fragments C3a and C5a.
Cytotoxic Leukocytes
Cytotoxic leukocytes include
Natural killer (NK) cells:
Typical NK cells constitute 5 to 15% of peripheral blood mononuclear cells. They have a round nucleus and granular cytoplasm and induce apoptosis in infected or abnormal cells by a number of pathways. As cells of the innate response, they lack antigen-specific receptors and immunologic memory. NK cells are best characterized by CD2+, CD3-, CD4-, CD8+, CD16+ (a receptor for IgG-Fc), and CD56+ surface markers.
Typical NK cells are thought to be important for tumor surveillance. NK cells express both activating and inhibitory receptors. The activating receptors on NK cells can recognize numerous ligands on target cells (eg, MHC class I–related chain A [MICA] and chain B [MICB]); the inhibitory receptors on NK cells recognize MHC class I molecules. NK cells can kill their target only when there is no strong signal from inhibitory receptors. MHC class I molecules (normally expressed on nucleated cells) therefore prevent destruction of cells; their absence indicates that the cell is infected with certain viruses that inhibit MHC expression or has lost MHC expression because cancer has changed the cell.
NK cells can also secrete several cytokines (eg, IFN-γ, IL-1, TNF-α); they are a major source of IFN-γ. By secreting IFN-γ, NK cells can influence the acquired immune system by promoting differentiation of type 1 helper T (TH1) cells and inhibiting that of type 2 (TH2) cells.
Lymphokine-activated killers (LAK):
Some leukocytes develop into potent lymphokine-activated killers, capable of killing a wide spectrum of tumor target cells and abnormal lymphocytes (eg, infected with certain viruses). These cells are a phenomenon rather than a unique subset of cells. LAK precursors are heterogeneous but can be classified primarily as NK-like (most common) or T-cell–like.
Lymphocytes
The 2 main types of lymphocytes are
They are morphologically indistinguishable but have different immune functions. They can be distinguished by Ag-specific surface receptors and molecules called clusters of differentiation (CDs), whose presence and absence define some subsets. More than 300 CDs have been identified (for further information on CD Ags, see the Human Cell Differentiation Molecules web site at hcdm.org/). Each lymphocyte recognizes a specific Ag via surface receptors.
B cells:
About 5 to 15% of lymphocytes in the blood are B cells; they are also present in the spleen, lymph nodes, and mucosa-associated lymphoid tissues. B cells can present Ag to T cells, but their primary function is to develop into plasma cells, which manufacture and secrete antibodies (Abs—see Biology of the Immune System: Antibodies).
After random rearrangement of the genes that encode immunoglobulin (Ig), B cells have the potential to recognize an almost limitless number of unique Ags. Gene rearrangement occurs in programmed steps in the bone marrow during B-cell development. The process starts with a committed stem cell, continues through pro-B and pre-B cell stages, and results in an immature B cell. If an immature B cell interacts with Ag, it may become inactivated (tolerant) or be eliminated (by apoptosis). Immature B cells that are not inactivated or eliminated may continue to develop into mature naive B cells, leave the marrow, and enter peripheral lymphoid organs, where they may encounter Ag. Their response to Ag has 2 stages:
T cells:
T cells develop from bone marrow stem cells that travel to the thymus, where they go through rigorous selection. There are 3 main types of T cell:
In selection, T cells that react to self Ag presented by self MHC molecules or to self MHC molecules (regardless of the Ag presented) are eliminated by apoptosis. Only T cells that can recognize nonself Ag complexed to self MHC molecules survive; they leave the thymus for peripheral blood and lymphoid tissues.
Most mature T cells express either CD4 or CD8 and have an Ag-binding, Ig-like surface receptor called the T-cell receptor (TCR). Genes that encode the TCR, like Ig genes, are rearranged, resulting in defined specificity and affinity for the Ag peptide displayed in the MHC molecule of an APC. As for B cells, the number of T-cell specificities is almost limitless.
For T cells to be activated, the TCR must engage with Ag-MHC. Costimulatory accessory molecules must also interact; otherwise, the T cell becomes anergic or dies by apoptosis. Some accessory molecules (eg, CTLA-4) inhibit previously activated T cells and thus dampen the immune response.
Helper T (TH) cells are usually CD4 but may be CD8. They differentiate from TH0 cells into one of the following:
Each cell type secretes several cytokines (see Table 1: Biology of the Immune System: Functions of T Cells ). Different patterns of cytokine production identify other TH-cell functional phenotypes.
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Table 1
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| Functions of T Cells |
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Type
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Substances Produced
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Primary Function
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TH1
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IFN-γ
IL-2
Lymphotoxin
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Facilitate macrophage and cytotoxic T-cell responses
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TH2
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IL-4
IL-5
IL-6
IL-10
IL-13
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Stimulate antibody production by B cells
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TH17
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IL-17
IL-21
IL-22
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Promote inflammatory responses
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Regulatory
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TGF-β
IL-10
IL-35
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Suppress immune responses
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TC
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Perforin
Granzymes
FasL
Cytokines
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Kill infected cells
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Activated NK T cells
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IL-4
IFN-γ
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May help regulate immune responses
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FasL = Fas ligand; IFN = interferon; IL = interleukin; NK = natural killer; TC
= cytotoxic T cell; TGF = transforming growth factor; TH
= helper T cell.
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The distinction between the different TH cells is clinically relevant. For example, a TH1 response dominates in tuberculoid leprosy, and a TH2 response dominates in lepromatous leprosy. A TH1 response is characteristic of certain autoimmune disorders (eg, type 1 diabetes, multiple sclerosis), and a TH2 response promotes IgE production and development of allergic disorders, as well as helps B cells produce autoantibodies in some autoimmune disorders (eg, Graves' disease, myasthenia gravis). TH17 cells, via their role in inflammation, may also contribute to autoimmune disorders.
Regulatory T cells mediate suppression of immune responses. The process involves functional subsets of CD4 T cells that either secrete cytokines with immunosuppressive properties or suppress the immune response by poorly defined mechanisms that require cell-to-cell contact. Some regulatory T cells express the CD8 T-cell phenotype.
Cytotoxic T (TC) cells are usually CD8 but may be CD4; they are vital for eliminating intracellular pathogens, especially viruses. TC cells play a role in organ transplant rejection.
TC-cell development involves 3 phases:
Fully activated TC cells, like NK cells, can kill an infected target cell by inducing apoptosis.
TC cells may be
Some TC cells can directly recognize foreign MHC (direct pathway); others may recognize fragments of foreign MHC presented by self MHC molecules of the transplant recipient (indirect pathway).
NK T cells are a distinct subset of T cells. Activated NK T cells secrete IL-4 and IFN-γ and may help regulate immune responses.
Antibodies
Abs act as the Ag receptor on the surface of B cells and, in response to Ag, are subsequently secreted by plasma cells. Abs recognize specific configurations (epitopes, or antigenic determinants) on the surfaces of Ags (eg, proteins, polysaccharides, nucleic acids). Abs and Ags fit tightly together because their shape and other surface properties (eg, charge) are complementary. The same Ab molecule can cross-react with related Ags if their epitopes are similar enough to those of the original Ag.
Structure:
Abs consist of 4 polypeptide chains (2 identical heavy chains and 2 identical light chains) joined by disulfide bonds to produce a Y configuration (see Fig. 2: Biology of the Immune System: B-cell receptor. ). The heavy and light chains are divided into a variable (V) region and a constant (C) region.
V regions are located at the amino-terminal ends of the Y arms; they are called variable because the amino acids they contain are different in different Abs. The amino acids present determine the specificity of the Ig. Hypervariable regions within the V regions contain idiotypic determinants, to which certain natural (anti-idiotype) Abs can bind; this binding may help regulate B-cell responses. A B cell can switch the Ig heavy chain isotype it produces, but it retains its heavy chain V region and the entire light-chain, thereby retaining antigenic specificity.
The C region contains a relatively constant sequence of amino acids that is distinctive for each Ig isotype.
The amino-terminal (variable) end of the Ab binds to Ag to form an Ab-Ag complex. The Ag-binding (Fab) portion of Ig consists of a light chain and a fragment of a heavy chain and contains the V region of the Ig molecule (ie, the combining sites). The crystallizable fragment (Fc) contains most of the C region of the heavy chains; Fc is responsible for complement activation and binds to Fc receptors on cells.
Antibody classes:
Antibodies are divided into 5 classes:
The classes are defined by their type of heavy chain (μ for IgM, γ for IgG, α for IgA, ε for IgE, and δ for IgD); there are also 2 types of light chains (κ and λ). Each of the 5 Ig classes can bear either κ or λ light chains.
IgM is the first Ab formed after exposure to new Ag. It has 5 Y-shaped molecules (10 heavy chains and 10 light chains), linked by a single joining (J) chain. IgM circulates primarily in the intravascular space; it complexes with and agglutinates Ag and can activate complement, thereby facilitating phagocytosis. Isohemagglutinins and many Abs to gram-negative bacteria are IgM. Monomeric IgM acts as a surface Ag receptor on B cells.
IgG is the most prevalent Ig isotype in serum and is present also in intravascular and extravascular spaces. It coats Ag to activate complement and facilitate phagocytosis by neutrophils and macrophages. IgG is the primary circulating Ig produced after reexposure to Ag (secondary immune response) and is the predominant isotype contained in commercial γ-globulin products. IgG protects against bacteria, viruses, and toxins; it is the only Ig isotype that crosses the placenta.
There are 4 subclasses of IgG: IgG1, IgG2, IgG3, and IgG4. They are numbered in descending order of serum concentration. IgG subclasses differ functionally mainly in their ability to activate complement; IgG1 and IgG3 are most efficient, IgG2 is less efficient, and IgG4 is inefficient. IgG1 and IgG3 are efficient mediators of Ab-dependent cellular cytotoxicity; IgG4 and IgG2 are less so.
IgA occurs at mucosal surfaces, in serum, and in secretions (saliva; tears; respiratory, GU, and GI tract secretions; colostrum), where it provides an early antibacterial and antiviral defense. J chain links IgA into a dimer to form secretory IgA. Secretory IgA is synthesized by plasma cells in the subepithelial regions of the GI and respiratory tracts.
IgD is coexpressed with IgM on the surface of naive B cells. Whether these 2 classes function differently on the surface of the B cell and, if so, how differently are unclear. They may simply be an example of molecular degeneracy. Serum IgD levels are very low, and the function of circulating IgD is unknown.
IgE is present in low levels in serum and in respiratory and GI mucous secretions. IgE binds with high affinity to receptors present in high levels on mast cells and basophils and to a lesser extent on several other hematopoietic cells, including dendritic cells. If Ag bridges 2 IgE molecules bound to the mast cell or basophil surface, the cells degranulate, releasing chemical mediators that cause an inflammatory response. IgE levels are elevated in atopic disorders (eg, allergic or extrinsic asthma, hay fever, atopic dermatitis) and parasitic infections.
Acute Phase Reactants
Acute phase reactants are plasma proteins whose levels dramatically increase if infection or tissue damage occurs. Most dramatically increased are C-reactive protein and mannose-binding lectin (which fix complement and act as opsonins), the transport protein α1-acid glycoprotein, and serum amyloid P component. Many acute phase reactants are made in the liver. Collectively, they may help limit tissue injury, enhance host resistance to infection, and promote tissue repair and resolution of inflammation.
Cytokines
Cytokines are polypeptides secreted by immune and other cells when the cell interacts with a specific Ag, endotoxin, or other cytokines. Main categories include
Although lymphocyte interaction with a specific Ag triggers cytokine secretion, cytokines themselves are not Ag-specific; thus, they bridge innate and acquired immunity and generally influence the magnitude of inflammatory or immune responses. They act sequentially, synergistically, or antagonistically. They may act in an autocrine or paracrine manner.
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Table 2
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| Selected Cytokines |
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Cytokine
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Major Sources
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Main Effects
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Interleukins (IL)
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IL-1α
IL-1β
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B cells, dendritic cells, endothelium, macrophages, monocytes, NK cells
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Costimulates T-cell activation by enhancing production of cytokines (eg, IL-2 and its receptor)
Enhances B-cell proliferation and maturation
Enhances NK-cell cytotoxicity
Induces IL-1, IL-6, IL-8, TNF, GM-CSF, and prostaglandin E2 production by macrophages
Is proinflammatory by inducing chemokines, ICAM-1, and VCAM-1 on endothelium
Induces sleep, anorexia, release of tissue factor, acute phase reactants, and bone resorption by osteoclasts
Is an endogenous pyrogen
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IL-2
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TH1 cells
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Induces proliferation of activated T and B cells
Enhances NK-cell cytotoxicity and killing of tumor cells and bacteria by monocytes and macrophages
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IL-3
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Mast cells, NK cells, T cells
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Induces growth and differentiation of hematopoietic precursors and growth of mast cells
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IL-4
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Mast cells, NK cells, NK-T cells, γ
δ T cells, TC2 cells, TH2 cells
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Induces TH2 cells
Stimulates proliferation of activated B, T, and mast cells
Upregulates class II MHC molecules on B cells and on macrophages and CD23 on B cells
Downregulates IL-12 production and thereby inhibits TH1 cell-differentiation
Increases macrophage phagocytosis
Induces switch to IgG1 and IgE
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IL-5
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Mast cells, TH2 cells
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Induces proliferation of eosinophils and activated B cells
Induces switch to IgA
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IL-6
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Dendritic cells, fibroblasts, macrophages, monocytes, TH2 cells
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Induces differentiation of myeloid stem cells and B cells into plasma cells
Induces acute phase reactants
Enhances T-cell proliferation
Induces TC-cell differentiation
Is a pyrogen
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IL-7
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Bone marrow and thymus stromal cells
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Induces differentiation of lymphoid stem cells into T- and B-cell precursors
Activates mature T cells
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IL-8 (chemokine)
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Endothelial cells, macrophages, monocytes
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Mediates chemotaxis and activation of neutrophils
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IL-9
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TH cells
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Induces proliferation of thymocytes
Enhances mast cell growth
Acts synergistically with IL-4 to induce switch to IgG1 and IgE
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IL-10
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B cells, macrophages, monocytes, TC cells, TH2 cells
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Inhibits IL-2 secretion by human TH1 cells
Downregulates production of class II MHC molecules and cytokines (eg, IL-12) by monocytes, macrophages, and dendritic cells and thereby inhibits TH1-cell differentiation
Inhibits T-cell proliferation
Enhances B-cell differentiation
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IL-11
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Bone marrow stromal cells
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Promotes differentiation of pro-B cells and megakaryocytes
Induces acute phase reactants
Stimulates macrophage precursors
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IL-12
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B cells, dendritic cells, macrophages, monocytes
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Critical for TH1 differentiation
Induces proliferation of TH1 cells, CD8 T cells, γ
δ T cells, and NK cells and their production of IFN-γ
Enhances NK and CD8 T-cell cytotoxicity
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IL-13
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Mast cells, TH2 cells
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Inhibits activation and cytokine secretion by macrophages
Coactivates B-cell proliferation
Upregulates class II MHC molecules and CD23 on B cells and monocytes
Induces switch to IgG1 and IgE
Induces VCAM-1 on endothelium
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IL-14
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—
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Originally thought to stimulate B cells, but gene and protein sequence have not been confirmed
IL-14 may not exist
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IL-15
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B cells, dendritic cells, macrophages, monocytes, NK cells, T cells
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Induces proliferation of T, NK, and activated B cells
Induces cytokine production and cytotoxicity of NK cells and CD8 T cells
Is chemotactic for T cells
Stimulates growth of intestinal epithelium
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IL-16
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TC cells, TH cells
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Is chemoattractant for CD4 T cells, monocytes, and eosinophils
Induces class II MHC molecules
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IL-17
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T cells
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Is proinflammatory
Stimulates production of cytokines (eg, TNF, IL-1β, IL-6, IL-8, G-CSF)
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IL-18
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Monocytes, dendritic cells
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Induces IFN-γ production by T cells
Enhances NK-cell cytotoxicity
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IL-19
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B cells, monocytes, macrophages
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Induces proliferation and proinflammatory activities in keratinocytes
Promotes TH2-cell responses
Induces apoptosis in monocytes
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IL-20
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Keratinocytes, macrophages
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Induces proliferation and proinflammatory activities in keratinocytes
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IL-21
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NK cells, TH cells
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Stimulates B-cell proliferation after CD40 cross-linking
Stimulates proliferation of bone marrow precursor cells
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IL-22
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Mast cells, NK cells, T cells
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Is proinflammatory
Induces synthesis of acute phase reactants
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IL-23
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Dendritic cells, macrophages
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Induces proliferation of TH cells
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IL-24
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B cells, macrophages, monocytes, T cells
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Suppresses tumor cell growth
Induces apoptosis in tumor cells
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IL-25
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Bone marrow stromal cells
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Induces production of cytokines that promote eosinophilia
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IL-26
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T cells
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Is proinflammatory
Induces IL-8 and IL-10 production and ICAM-1 expression in epithelial cells
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IL-27
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Dendritic cells, macrophages
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Induces TH1 cells
Is a heterodimer consisting of IL-30 and Epstein-Barr virus–induced gene 3
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IL-28
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Mononuclear cells in response to viral infection
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Is antiviral
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IL-29
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Mononuclear cells in response to viral infection
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Is antiviral
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IL-30
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Dendritic cells, macrophages
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Induces TH1 cells
Is a subunit of IL-27
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Interferons (IFN)
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IFN-α
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Leukocytes
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Inhibits viral replication
Increases class I MHC expression
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IFN-β
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Fibroblasts
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Inhibits viral replication
Increases class I MHC expression
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IFN-γ
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NK cells, TC1 cells, TH1 cells
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Inhibits viral replication
Increases class I and II MHC expression
Activates macrophages
Antagonizes several actions of IL-4
Inhibits proliferation of TH2 cells
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Tumor necrosis factors (TNF)
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TNF-α (cachectin)
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B cells, dendritic cells, macrophages, mast cells, monocytes, NK cells, TH cells
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Is cytotoxic to tumor cells
Causes cachexia
Induces secretion of several cytokines (eg, IL-1, GM-CSF, IFN-γ)
Induces E-selectin on endothelium
Activates macrophages
Is antiviral
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TNF-β (lymphotoxin)
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TC cells, TH1 cells
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Is cytotoxic to tumor cells and antiviral
Enhances phagocytosis by neutrophils and macrophages
Is involved in lymphoid organ development
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Colony-stimulating factors (CSF)
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G-CSF
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Endothelial cells, fibroblasts
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Stimulates growth of neutrophil precursors
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GM-CSF
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Endothelial cells, fibroblasts, macrophages, mast cells, TH cells
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Stimulates growth of precursors of monocytes, neutrophils, eosinophils, and basophils
Activates macrophages
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M-CSF
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Endothelial cells, epithelial cells, fibroblasts
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Stimulates growth of monocyte precursors
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SCF
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Bone marrow stromal cells
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Stimulates stem cell division
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Transforming growth factors (TGF)
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TGF-α
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Monocytes, solid tumors (carcinoma more so than sarcomas)
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Induces angiogenesis, keratinocyte proliferation, bone resorption, and tumor growth
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TGF-β
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B cells, macrophages, mast cells, TH3 cells
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Is proinflammatory (eg, by chemoattraction of monocytes and macrophages) but also anti-inflammatory (eg, by inhibiting lymphocyte proliferation)
Induces switch to IgA
Promotes tissue repair
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NK = natural killer; TNF = tumor necrosis factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; ICAM-1 = intercellular adhesion molecule 1; VCAM-1 = vascular cell adhesion molecule 1; TH cell = helper T cell; TC cell = cytotoxic T cell; MHC = major histocompatibility complex; CD = cluster of differentiation; G-CSF = granulocyte colony-stimulating factor; SCF = stem cell factor.
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Cytokines deliver their signals via cell surface receptors. For example, the IL-2 receptor consists of 3 chains: α, β, and γ. The receptor's affinity for IL-2 is high if all 3 chains are expressed, intermediate if only the β and γ chains are expressed, or low if only the α chain is expressed. Mutations or deletion of the γ chain is the basis for X-linked severe combined immunodeficiency (see Immunodeficiency Disorders: Severe Combined Immunodeficiency (SCID)).
Chemokines induce chemotaxis and migration of leukocytes. There are 4 subsets, defined by the number of intervening amino acids between the first 2 cysteine residues in the molecule. Chemokine receptors (CCR5 on memory T cells, monocytes/macrophages, and dendritic cells; CXCR4 on resting T cells) act as coreceptors for entry of HIV into cells.
Last full review/revision September 2008 by Peter J. Delves, PhD
Content last modified September 2008
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