ACP medicine, 3rd Edition

Immunology/Allergy

Cell-Cell Interactions, Cytokines, and Chemokines in Immune Response Mechanisms

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 chapter.

July 2004

The immune response is defined by three principles: discrimination between self and nonself, specificity, and memory [see 6:I Organs and Cells of the Immune System]. This chapter will discuss the manifestation of those principles through antigen processing and presentation, the T cell response to antigen, interactions between T cells and B cells, and the actions of cytokines and chemokines. The cellular and humoral mechanisms of innate immunity are described in detail elsewhere [see 6:II Innate Immunity].

Two principal arenas of the immune response are sites of pathogenic invasion and the lymph nodes that drain these sites. The immune response begins with exposure of epithelial cells, macrophages, and dendritic cells to a pathogen. In the lymph nodes, these cells (antigen-processing cells [APCs]) concentrate and process antigens and present them to T and B cells.

The critical first step of the T cell immune response to a specific antigen is the recognition and binding of processed antigen on the surface of an APC with a T cell receptor (TCR) on the surface of a helper (CD4+) T cell [see 6:I Organs and Cells of the Immune System]. This event is relayed to the helper T cell nucleus by a cascade of cytoplasmic signaling molecules. In the nucleus, activation of specific transcription factors stimulates expression of the genes that encode soluble factors—cytokines and chemokines—that mediate the immune response. This response has two aspects: humoral and cell mediated. In the humoral response, cytokines secreted by a specific form of activated T cells induce antigen-stimulated B cells to differentiate into antibody-secreting plasma cells. In the cell-mediated response, cytokines from CD4+ T cells induce CD8+ T cells to differentiate into cytolytic effectors and also can activate macrophages, another effector cell. B cells recognize nonprocessed antigens in solution or antigens that are attached to the surface of follicular dendritic cells—a cell type that is particularly adept at antigen processing, presentation, and retention. Both T cells and B cells are induced to expand their population and control the initial infection and to produce memory cells for long-term acquired immunity.

Antigen Processing and Presentation

THE MAJOR HISTOCOMPATIBILITY COMPLEX

The major histocompatibility complex (MHC) is a membrane glycoprotein complex that binds antigenic peptide in the cytoplasm of an APC and transports it to the cell surface for interaction with T cells.1 An extensive polymorphism exists in the MHC gene (i.e., there are many alleles per locus); however, each person expresses only a small number of different MHC molecules. To ensure an adequate immune response against a wide range of nonself antigens, each MHC molecule must be able to bind a large number of different peptides.

Two main classes of MHC have been identified. The two classes of molecules have a similar structure: two immunoglobulin-like domains and a binding site for processed antigens (peptides) [see 6:V Adaptive Immunity: Histocompatibility Antigens and Immune Response Genes]. Whereas MHC class I molecules bind only smaller peptides of defined lengths (eight to 11 amino acids), MHC class II molecules bind longer peptides with no apparent restriction on peptide length. An interesting finding is that certain peptides bind only to specific alleles of either MHC class I or MHC class II molecules. Thus, persons who lack one of those alleles would not develop an immune response to its associated peptide.

The differences in peptide binding between MHC class I and MHC class II molecules result from small structural dissimilarities within the relatively fixed framework of the peptide-binding site and probably also from fundamental differences in the mechanism of peptide processing, which takes place in the endoplasmic reticulum (ER) for MHC class I molecules and in the endosomes and lysosomes for MHC class II molecules.

The MHC Class I Pathway

Antigen processing with MHC class I molecules essentially entails three steps: (1) generation of antigenic peptides in the cytosol of the APC, (2) transport of the peptides into the ER, and (3) assembly of the peptide-MHC class I complexes. The completed complexes then migrate through the Golgi apparatus to the cell surface and insert in the plasma membrane for presentation on the extracellular surface [see Figure 1, part a].

 

Figure 1. Pathways for Formation of Antigenic Peptide-MHC Molecule Complexes

The pathways for formation of antigenic peptide-MHC molecule complexes on antigen-presenting cells. (a) In the MHC class I molecule pathway, endogenous proteins are broken down by proteasomes into smaller peptides. In the endoplasmic reticulum (ER), an antigenic peptide binds to the peptide binding site in an MHC class I molecule. The peptide-MHC complex then migrates through the Golgi apparatus to the cell surface. (b) In the MHC class II molecule pathway, the α and β subunits of the MHC class II molecule bind to the invariant chain (Ii) in the ER. Ii is partially degraded in an endosomal compartment. The portion of Ii that occupies the antigenic peptide binding site on the MHC class II molecule (called CLIP) is removed with the help of HLA-DM, freeing the molecule for binding processed antigen. Once antigenic peptide has bound to an MHC class II molecule, the complex migrates to the cell surface.

The MHC Class II Pathway

Assembly of antigenic peptide-MHC class II molecule complexes in the APC requires four steps: (1) uptake of exogenous antigens by vesicles (endosomes, lysosomes, and, possibly, undefined endosomal subcompartments), (2) proteolytic degradation of proteins in the endosome, (3) assembly of MHC class II molecules in the ER and migration of these molecules through the Golgi apparatus to the endosomes, and (4) assembly of the peptide-MHC class II complexes in the late endosome. After the peptides are bound to MHC class II molecules, the endosome containing these complexes migrates to the cell surface and inserts in the plasma membrane [see Figure 1, part b]. Of note is that partially unfolded antigenic proteins can bind to MHC class II molecules before undergoing proteolytic degradation. This may explain why the length of peptides bound to MHC class II molecules is highly variable.

ALTERNATIVE ANTIGEN-PRESENTING COMPLEXES

A third class of MHC includes CD1 molecules, which are related to MHC class I molecules but which bind lipid and glycolipid antigens for presentation to T cells. For example, CD1 molecules present glycolipids from Mycobacterium tuberculosis to a restricted group of T cells.2This ability to recognize nonprotein microbial antigens suggests that T cells recognize a broader range of antigens than was once thought. A subset of CD1+ T cells often reacts to self-antigens; these cells have been implicated in such autoimmune diseases as type 1 diabetes mellitus and systemic lupus erythematosus. It has been suggested that they are involved at the early innate phase of these immune responses.3 Another molecule related to MHC class I, MR1, is found on a subset of T cells that are preferentially located in the gut lamina propria and are called mucosal-associated invariant T (MAIT) cells. MAIT cells are probably involved in the host response at the site of pathogen entry and may regulate intestinal B cell activity. MAIT cells are absent in humans and mice that have B cell deficiency, which suggests that the selection or expansion of this cell population requires B cells.4

Superantigens

Superantigens constitute a class of immunostimulatory proteins derived from microbial agents (e.g., viral proteins and the staphylococcal toxins that cause toxic-shock syndrome and food poisoning). Superantigens bind to MHC class II molecules outside the conventional antigen-binding site and stimulate massive T cell activation5 [see 7:XXX Sepsis]. Different MHC class II alleles have distinct binding constants for superantigens; thus, superantigens can activate distinct segments of the T cell repertoire.

PROFESSIONAL ANTIGEN-PRESENTING CELLS

Whereas MHC class I molecules are expressed on the surface of all eukaryotic cells, MHC class II molecules have a restricted tissue distribution. In fact, certain cells—including B cells, dendritic cells, macrophages, Langerhans cells, and endothelial cells—are termed professional APCs because they present antigenic peptide with MHC class II molecules more efficiently than other APCs.6 This efficiency is primarily attributed to their ability to process endocytosed antigens. Professional APCs also interact with T cells more efficiently because they have several cell surface markers that bind to costimulatory molecules on the surface of T cells (see below). The most potent APCs are dendritic cells, which present antigen only on maturation and migration to the lymph nodes. This maturation process is triggered by the uptake of antigen.

T Cell Responses to Antigen

T cell recognition of antigen proceeds in two distinct stages. The first step, which is nonspecific, is the adhesion of a T cell to an APC. The second step, which is specific, is an interaction between the TCR and a compatible antigen-MHC complex on the APC. This process highlights two fundamental properties of T cells: their broad scope of action (i.e., their ability to migrate throughout the body and adhere to many types of cells) and their great specificity for particular antigens.

The diversity of the variable regions in TCRs facilitates highly specific responses to antigens [see 6:III Adaptive Immunity: Antigens, Antibodies, and T Cell and B Cell Receptors]. The prototypical T cells, αβ T cells, have a TCR made up of α and β chains, which are expressed in association with CD3. A subset of peripheral T cells, γδ T cells—so called because their TCR is made up of γ and δ chains—may recognize antigen that has not been processed.

APCs process many peptide antigens simultaneously and thus express on their cell surfaces a large number of different antigen-MHC complexes. A given αβ T cell clone can recognize only a small number of these complexes. T cells screen APCs for compatible antigen-MHC complexes by adhering to the APC. Adhesion is aborted if the TCRs do not recognize specific antigen; adhesion is intensified when a TCR makes contact with a compatible antigen-MHC complex. On adhesion, TCR-CD3 complexes aggregate on the surface of the T cell and bind to the antigen-MHC complexes that have aggregated on the surface of the APC. In the absence of antigen recognition, TCR-CD3 complexes are unable to cluster and detachment occurs immediately.

Interactions between a helper T cell clone and an APC or between a cytotoxic T cell and its target cell follow the same general pattern. Initially, only a very small number of antigen-MHC complexes engage with specific TCRs in an area of cell-cell contact established by adhesion. Subsequently, TCR-CD3 complexes and MHC molecules bearing the correct antigenic peptide migrate into the contact region. This establishes a high local density of TCRs, which promotes antigen binding and T cell activation. The existence of these clustered TCRs has been demonstrated experimentally, through the use of tagged mono clonal antibodies.7 In addition, visualization of clusters of TCRs using fluorescence-tagged antigen-MHC complexes has permitted incisive studies of T cell responses to infections with Epstein-Barr virus or HIV.8,9

COSTIMULATORY MOLECULES

The recognition of antigen by the TCR and subsequent activation of the T cell is regulated by other T cell surface molecules [see Figure 2]and [see Table 1].10 Costimulatory molecules are involved in both adhesion and T cell signaling and play a major role in the coordination and kinetic regulation of T cell activation. Clinically, these costimulatory molecules are important because aberrant activation of the TCR can initiate disastrous immune responses, such as those seen in autoimmune diseases.

 

Figure 2. Activation of Antigen-Specific T Cell

(a) Two signals are necessary for activation of an antigen-specific T cell by an antigen-presenting cell (APC). Signal 1 is initiated by the interaction between the antigen bound to a class II major histo compatibility complex (MHC) and the T cell receptor (TCR) and its coreceptor (in this example, CD4). The costimulatory molecules B7-1 and B7-2 are transiently expressed on the surface of so-called professional APCs and are presumed to be inducible by signaling from the antigen-MHC complex. Thus, signal 2 is initiated by the binding of CD28 on the T cell to B7-1 or B7-2. CTLA-4, which is homologous to CD28, is upregulated after T cell activation. (b) Activation of B cells can occur with either helper T cells or soluble antigen. Binding of soluble antigen to the B cell receptor, a cell surface immunoglobulin associated with Igα and Igβ, can lead to B cell proliferation or apoptosis. Alternatively, B cells can process antigen for presentation to TCRs on T cells. Binding of antigen-MHC complex to the TCR induces expression of the CD40 ligand (CD154) on the T cell surface, which in turn induces expression of CD40 on the B cell surface. This results in B cell proliferation and is indispensable for immunoglobulin class switching and probably for somatic mutation. CD154 signaling also plays an important role in the maturation of dendritic cells. (ICAM-1—intercellular adhesion molecule-1; LFA—leukocyte-function-associated antigen)

Table 1 Costimulatory Molecules on T Cells

Molecule

Ligand

Function

CD4

MHC molecules on the surface of APCs

Helps generate CD4+ T cells in the thymus; directly influences TCR-initiated signaling

CD8

MHC molecules on the surface of APCs

Helps generate CD8+ T cells in the thymus; directly influences TCR-initiated signaling

CD2

CD58 on the surface of APCs

Promotes T cell activation and proliferation

CD11/CD18

ICAM-1 (CD54), the complement component iC3b, extracellular matrix proteins

Promotes T cell activation and proliferation

CD28

B7-1 (CD80), B7-2 (CD86) on the surface of APCs

Promotes T cell activation and proliferation

CTLA-4

B7-1 (CD80), B7-2 (CD86) on the surface of APCs

Inhibits T cell activation and proliferation

SLAM*

SLAM receptors on the surface of APCs

Promotes activation and proliferation of T cells and other immune cells

CD27

CD70 on activated T and B cells

T cell proliferation

Fas (APO-1; CD95)

CD95L on cytolytic effector cells

Causes apoptosis or promotes TCR-CD3 activation

*Also found on natural killer cells.
APC—antigen-presenting cell CTLA-4—cytotoxic T lymphocyte–associated antigen-4 ICAM-1—intercellular adhesion molecule-1 SLAM—signaling lymphocyte activation molecule TCR—T cell receptor

The costimulatory molecules CD28 and cytotoxic T cell-associated antigen 4 (CTLA-4) initiate a signaling pathway that is different from, and often independent of, the pathway mediated by the TCR-CD3 complex. CD28 is expressed on the surface of essentially all CD4+ and most CD8+ T cells. CD28 binds to B7 on APCs, leading to T cell activation and proliferation. Although CTLA-4 is homologous to CD28, it has opposite effects: binding of CTLA-4 to B7 delivers an inhibitory signal that leads to downregulation of T cell proliferation. Of note is that research entailing manipulation of CD28-CTLA-4 interactions with their natural ligands suggests that these costimulatory molecules have a potential role in the treatment of such diseases as arthritis, multiple sclerosis, and asthma and in protection against HIV infection.11 For example, a soluble construct of CTLA-4 (called CTLA-4-Ig) is able to inhibit T cell activation when administered early in the immune response. Several new members of the B7 and CD28-CTLA-4 families have recently been discovered, and these may also be important for regulating the responses of previously activated T cells.12

The SLAM (signaling lymphocyte activation molecule) family of receptors serves as costimulatory molecules on T cells (and other immune cells). In T cells and natural killer (NK) cells, SLAM-associated protein (SAP) regulates signaling of the SLAM family of receptors. The SAP(or SH2D1A) gene is defective or absent in patients with X-linked lymphoproliferative syndrome.13,14

Fas (also called APO-1 and CD95) has been implicated in both positive and negative signaling events after binding with its ligand (CD95L) on cytolytic effector cells. Fas is a member of the tumor necrosis factor receptor (TNFR) family, and binding of Fas on T cells with its ligand typically causes the program med death of the target cell (i.e., apoptosis; see below). However, Fas can also function as a costimulatory molecule for TCR-CD3 activation. Thus, a single molecule can have different signaling outcomes at different stages of T cell development.

T Cell Signaling after Antigen Recognition

In response to antigen recognition, resting T cells undergo a complex series of events known as T cell activation.15,16 The recognition and binding of TCRs to antigen-MHC complexes and of costimulatory molecules to their appropriate ligands—all of which takes place on the cell surface—is followed by an intracellular cascade of biochemical events (i.e., signal transduction) that ultimately reaches specific genes in the nucleus. The resulting production of cytokines, chemokines, and other immunomodulatory molecules leads to cell proliferation, differentiation, and expression of unique effector functions.

Most of the biochemical events that occur immediately after engagement of the TCR with the antigen-MHC complex have been defined [seeFigure 3]. Transduction of signals starts with the CD3 elements of the TCR-CD3 complex and proceeds to the nucleus via different pathways. One pathway involves the calcium-dependent enzyme calcineurin; other coupled pathways involve the enzymes Ras and Rac and serine-threonine kinase. These pathways converge on the activation of transcription factors that control the expression of genes mediating T cell effector function (e.g., the gene for the cytokine interleu kin-2 [IL-2]) [see Figure 3]. Thus, the exquisitely T cell clone-specific TCR connects, via a number of intermediate molecules, with universal signal transduction pathways.

 

Figure 3. Downstream Signaling Pathways

The downstream signaling pathways induced after TCR stimulation are shown. Phosphorylation of the cytoplasmic tails of the CD3-γ, CD3-δ, CD3-ε, and CD3-ξ by the Src kinase Fyn or Lck recruits the kinase Syk or ZAP-70, which relays the signal of TCR binding through tyrosine phosphorylation of two adapter proteins, LAT and SLP-76. Nck is an adapter protein associated with SLP-76. These adapter proteins act on components of classic signal transduction pathways, including phospholipase C-γ1 (PLC-γ1), growth factor receptor-bound protein-2 (Grb-2, a protein-linking receptor tyrosine kinase), the p85 subunit of phosphatidylinositol-3-kinase (PI-3 kinase), and possibly Vav (a guanosine triphosphate/guanosine diphosphate [GTP/GDP] exchange factor for Rho-family GTPases, including Ras and Rac). Activation of PLC-γ causes the release of diacylglycerol, which in turn activates protein kinase C (PKC). PKC is involved in initiating the cascade of other serine-threonine kinases, including Raf-1, mitogen-activated protein (MAP) kinase, and MAP kinase kinase (MEK). The central signal transduction molecule Ras appears to be involved in late events after PKC activation. The Ras and Rac pathways and the serine-threonine kinase pathways are coupled; they activate early genes, such as jun and fos. The Ca2+ generated by PLC-γ1 activates another downstream cascade, the calcineurin pathway. Calcineurin, a serine-threonine phosphatase, is a calcium- and calmodulin-dependent enzyme involved in induction of transcription factor NFAT (nuclear factor for activated T cells). PI-3 kinase is a ubiquitous enzyme in the mitogenic signaling and apoptotic pathways of both receptor and nonreceptor protein tyrosine kinases. These various signaling pathways converge by delivering a distinct set of transcription factors, including Jun, Elk, NFAT, Fos, and AP-1 (all DNA-binding proteins), to the promoter region of the IL-2 gene, stimulating expression of the gene and production of IL-2.

Drugs are being developed to interfere with nodal points of these signal transduction pathways. However, cyclosporine, which interferes with the calcineurin pathway, remains the most successful agent of this type.

B Cell Responses to Antigen

When a B cell receptor (BCR) binds soluble antigen, one of two events takes place: apoptosis or proliferation and further maturation of B cells. The signals for these processes are generated intracellularly by Igα and Igβ. These proteins are associated with BCRs in the way that CD3 proteins are associated with TCRs. Igα and Igβ recruit signal transduction molecules in a manner similar to that for activating T cells and involving some of the same proteins.

Relatively little is known about the signaling that takes place in B cells when they have presented an antigen to a helper T cell that recognizes that antigen. T cell-B cell interaction can also lead to either apoptosis or proliferation of B cells. With T cell help, however, proliferation results in the generation of several different classes of B cells.

B CELL SUBSETS

Follicular Mantle Cells

Follicular mantle cells derive their name from their location, surrounding the active germinal centers in lymph nodes. These cells express IgD but not CD38 on their surface (i.e., they are IgD+, CD38-) and can mature into plasma cells that produce IgM antibodies only. These cells produce IgM antibodies that display extensive heterogeneity, but the cells do not undergo somatic mutation to generate larger numbers of heterogeneous antibody molecules.

Centrocytes

Centrocytes are found in the germinal center of lymph nodes. The process leading to somatic mutation occurs in the centrocytes, which are IgD-, CD38+ B cells that have undergone class switching to produce IgG. The maturation step from IgD+, CD38- B cells to IgD-, CD38+ B cells depends on cell-cell contact with antigen-specific T cells and cytokines. IL-4 in particular is of great importance for the events that lead to class switching.

Memory B Cells

The most mature B cell, the memory cell, does not express IgD or CD38 but is distinguished by the presence of other cell surface markers and by its location within the germinal center of lymph nodes. Memory cells can also develop into plasma cells producing IgM, IgG, IgA, and IgE. In general, the generation of plasma cells from memory B cells is independent of T cell help.

T Cell-B Cell Interactions

An important pathway for B cell activation involves CD40, a B cell surface receptor belonging to the TNFR family. The natural ligand for CD40, CD40L (also called CD154), is a glycoprotein related to TNF. Transient CD40L expression on the surface of T cells is induced by the binding of TCR to antigen-MHC complex and by binding of B7 to CD28 or CTLA-4. The binding of CD40 to CD40L stimulates B cell immunoglobulin class switching. This was best demonstrated by elucidation of the molecular defect in a genetic immunodeficiency termed hyper-IgM syndrome [see 6:VIII Deficiencies in Immunoglobulins and Cell-Mediated Immunity]. Patients with the X-linked form of this syndrome have a mutation in the gene encoding CD40L that results in defective antibody class switching. T cell-independent B cell responses and responses induced by anti-CD40 are unaffected by this mutation. Thus, T cell help for B cell activation is primarily directed through the CD40-CD40L costimulatory pathway. The observation that persons with hyper-IgM syndrome are susceptible to opportunistic infections such as those seen in AIDS—that is, infections from pathogens normally dealt with by T cells—underscores the role of CD40L costimulation in normal T cell activation. Absence of CD40L has a more dramatic effect on immunoglobulin class switching than does an absence of T cells. Thus, it seems that CD40L may be expressed on cells other than T cells that could induce immunoglobulin class switching in B cells through the ligation of CD40.

Cytokines

CYTOKINES AND T CELL SUBSETS

Cytokines, a diverse group of proteins produced by a number of different cell types, are critical in the regulation of immune responses [seeTable 2]. They are also important in the differentiation of cell systems. In general, cytokines are synthesized in response to stimulation of cells. In some cases, the active cytokine is released from an inactive precursor by proteolysis. Occasionally, cytokines are stored in cells.

Table 2 Selected Cytokines

Cytokine

Sources

Principal Functions

Comments

Interferon-γ (IFN-γ)

T cells, NK cells

Primary macrophage-activating factor (MAF)

Used to treat chronic granulomatous disease, drug-resistant leishmaniasis

Interleukin-1

Monocytes, macrophages, other cells

MAF, endogenous pyrogen

IL-1 inhibitors counteract rheumatoid arthritis and other inflammatory processes

Interleukin-2

Th1 cells

Activation of lymphocytes, NK cells; MAF

Used in cancer therapy

Interleukin-4

Th1 cells, other cells

Activation of lymphocytes, monocytes; B cell class switching

Interleukin-5

Th2 cells, activated mast cells

Eosinophil recruitment and activation

Interleukin-6

Th1 cells, macrophages

Activates T cells and macrophages, promotes inflammation

Interleukin-8

T cells, macrophages

Activates neutrophils

Interleukin-10

T cells, B cells, macrophages, activated mast cells, keratinocytes

Suppresses lymphocyte responses by downregulating macrophage cytokines

Interleukin-12

Macrophages

Stimulates development of Th1 cells, stimulates production of IFN-γ by Th1 and NK cells

Possible use as vaccine adjuvant

Interleukin-18

Macrophages

Stimulates production of IFN-γ

Lymphotoxin

Th1 cells

Lyses tumor cells, activates neutrophils, increases vascular adhesion and extravasation of leukocytes

Migration inhibitory factor

Macrophages, T cells

Counterregulates glucocorticoid action

Transforming growth factor–β

Platelets, lymphocytes, activated macrophages, placenta cells, others

Anti-inflammatory; inhibits activation of macrophages and maturation of cytotoxic T cells

Tumor necrosis factor–α

Macrophages, activated T cells, NK cells, mast cells

Enhances protective inflammatory response

Antibodies to TNFα are used in the treatment of Crohn disease and rheumatoid arthritis

NK—natural killer Th1—type 1 helper T cells Th2—type 2 helper T cells

After secretion, cytokines usually act locally by binding to receptors on cell surfaces. Cytokines may act on many different cells, and different cytokines may have similar activities. Cytokine receptors are often composed of the same protein chains. For instance, the cytokine receptors IL-2R, IL-4R, IL-7R, IL-9R, IL-13R, and IL-15R have the γ chain in common. Most cytokines form a network that regulates the activation of cells and the production of other cytokines.17 The binding of cytokines to receptors on cell surfaces activates intracellular signaling mechanisms, which lead to expression of particular genes (e.g., genes for the bound cytokine, or other cytokines). The principal intracellular cytokine signal transducers are two families of transcription factors: Jak (Janus kinase) protein tyrosine kinases and STAT (signal transducers and activators of transcription).

Helper T cells

Cytokines play a major role in T cell development and regulation. Indeed, the two helper T cell subsets, Th1 and Th2, are defined by the cytokines they produce [see 6:X Allergic Response]. Th1 and Th2 cells play key roles in determining the balance between host resistance and immunopathology.18 Th1 responses can help eradicate infectious agents, but a Th1-dominated response that is poorly effective or too prolonged can result in host damage. Th2 responses are primarily involved in allergic reactions, antibody production, and antibody class switching. They can limit potentially harmful Th1-mediated responses and may be part of the suppressor mechanism for exaggerated or inappropriate Th1 responses.19

Each of the two helper T cell subsets inhibits the development and function of the other. Interferon gamma (IFN-γ) produced by Th1 cells inhibits the development and function of Th2 cells, whereas IL-4 and IL-10 produced by Th2 cells inhibit the development and function of Th1 cells. IL-4 acts partly by downregulating the expression of the IL-12 receptor, IL-12Rβ, which is upregulated by IFN-γ [see Figure 4]. IL-12 enhances cell function because it is a potent growth factor for NK cells, which also produce IFN-γ. Presumably, the reason Th1 and Th2 cells inhibit each other is that both subsets also induce inflammation, which must be regulated [see Inflammatory Cytokines and Anti-inflammatory Cytokines, below].

 

Figure 4. Regulation of Helper T Cell Responses

Regulation of helper T cell responses. In response to IL-12 and cofactors such as IL-18 and IL-1a, naive CD4+ T cells can develop into type 1 helper T (Th1) cells responsible for cell-mediated immunity; differentiation is dependent on interferon gamma (IFN-γ). Th1 cells produce IFN-γ and IL-2. Th1 responses are directly antagonized by IL-4 and indirectly by IL-10, as it inhibits production of IL-12 and IL-18 by macrophages. Th2 cells, which are responsible for inducing antibody production by B cells and allergic responses, depend on IL-4 for differentiation from naive CD4+ T cells. Th2 cells produce IL-4, IL-5, IL-10, and IL-13. TGF-β can inhibit both Th1 and Th2 development. (MCP—monocyte chemoattractant protein; TGF—transforming growth factor)

Certain microorganisms may affect the relative balance of Th1 and Th2. For example, the parasite Schistosoma drives a strong Th2 immune response. A carbohydrate found on the surface of Schistosoma, lacto-N-fucopentaose-III (LNFP-III), induces expansion of B1 cells and secretion of large amounts of IL-10. Acting through macrophages, IL-10 both blocks development of Th1 cells and favors Th2 responses.20,21A related carbohydrate, lacto-N-neotetraose (LNnT)—which is found on other helminths, Helicobacter pylori, Neisseria meningitidis, and other microorganisms—has a mode of action similar to that of LNFP-III.22 LNFP-III is also found on the surface of cancer cells, and LNnT is found in human milk, which suggests that in these circumstances, as well, the two carbohydrates are being used to shut off the host's protective cell-mediated immune response. Logically, such carbohydrates may have therapeutic value for the inhibition of Th1-initiated autoimmune diseases.

MEMORY T CELLS

On reexposure to an antigen, memory cells mediate a faster and stronger immune response than naive T cells. Memory cells secrete a full range of cytokines and may show the same selection of cytokines as Th1 and Th2 cells.10 The requirements for proliferation and cytokine production in memory cells are not as strict as those for production in naive T cells, but optimum responses require costimulation.23 Memory T cells selectively migrate (home) to specific nonlymphoid tissues such as gut, skin, and lung. Those that home to the gut have specialized integrins (adhesion molecules) on their surface that mediate this migration [see 6:I Organs and Cells of the Immune System]. In the absence of antigenic stimulation, memory cells appear to persist as nondividing cells. A reencounter with an antigen can expand the population to a stable, higher level; competition from another antigen can decrease the population.23

REGULATORY T CELLS

Natural regulatory T (Treg) cells are a population of T cells that primarily regulate responses to self antigens by other T cells and, therefore, contribute to the maintenance of self-tolerance. For example, removal of certain Treg cells from the periphery of normal mice leads to spontaneous development of various autoimmune and inflammatory diseases (e.g., autoimmune thyroiditis, gastritis, type 1 diabetes mellitus, and inflammatory bowel disease). Treg cells function via secreted or membrane-bound transforming growth factor-β (TGF-β) and by secretion of IL-10.24

Most Treg cells are CD4+ and constitutively express CD25 on their surface. CD4+, CD25+ T cells are produced by the normal thymus as a functionally mature T cell subpopulation with a broad T cell repertoire; they can recognize both self and nonself antigens.25 The Foxp-3 gene serves as a marker of this natural regulatory population. However, induction of Treg cells also takes place in the periphery (adaptive Treg cells).26 Chronic activation of human CD4+ T cells in the presence of IL-10 gives rise to a subset of antigen-specific CD4+ T cell clones with low proliferative capacity that produce high levels of IL-10, low levels of IL-2, and no IL-4. These T cells, called type 1 regulatory T (Tr1) cells, suppress the proliferation of CD4+ T cells in response to antigen, which suppresses antigen-specific immune responses and actively downregulates a pathologic immune response.27

INFLAMMATORY CYTOKINES

Interleukin-12 and Interleukin-18

IL-12 is a critical cytokine that stimulates the differentiation of naive helper T cells into Th1 cells, and it stimulates NK cells and Th1 cells to produce IFN-γ. IL-12 also enhances the cytolytic function of cytolytic T cells and NK cells. IL-12 is produced by activated macrophages and dendritic cells, in response to a variety of microorganisms. It has been used experimentally as an adjuvant in vaccines aimed at stimulating Th1-induced cellular immunity. As with most cytokines, binding of IL-12 with its receptor generates signaling through the Jak and STAT pathways.

IL-18, which is produced by macrophages, also stimulates the production of IFN-γ but appears to be less necessary than IL-12; whereas IL-12-deficient mice are susceptible to Leishmania major infection, IL-18-deficient mice combat such infection normally, although their initial immune response is slow.28 Similarly, IL-12 is critical for immunity to cytomegalovirus, whereas IL-18 is not.29

Tumor Necrosis Factor-a

TNF-α, a major inflammatory cytokine, is one of the most abundant substances produced by macrophages after stimulation with IFN-γ, migration inhibitory factor (MIF), or bacterial lipopolysaccharide (LPS). TNF-α is also produced by activated T cells, NK cells, and mast cells.

At low concentrations, TNF-α enhances the protective inflammatory response, activating and enhancing the function of various leukocytes, including neutrophils, macrophages, and eosinophils. This can further stimulate macrophages to produce cytokines, including TNF-α itself, IL-1, IL-6, MIF, and a variety of chemotactic cytokines [see Chemokines, below]. TNF-α enhances expression of MHC class I molecules, potentiates cytotoxic T cell-induced cell lysis, functions as an endogenous pyrogen (i.e., induces fever, by direct and indirect actions on the brain), activates the clotting system and the production of acute-phase proteins by the liver, and can cause immunodeficiency through suppression of the bone marrow. When present for prolonged periods, TNF-α causes cachexia.

TNF-α plays a primary role in the host response to gram-negative bacteria. The LPS of these bacteria causes the release of MIF, which in turn enhances TNF-α production by macro phages. At low concentrations of LPS, TNF-α mediates a protective response. At high concentrations of LPS, however, TNF-α mediates disseminated intravascular coagulation—part of what is known as the Shwartzman reaction—and can cause death from shock.

Protective immunity to certain intracellular organisms, such as Leishmania, is enhanced by TNF-α, and TNF-α also has potent antiviral activity. However, many of the symptoms of malaria, especially of cerebral malaria, and some symptoms of HIV infection may be mediated by TNF-α. Antibodies to TNF-α have been approved for the treatment of Crohn disease and rheumatoid arthritis [see 4:IV Inflammatory Bowel Diseases and 15:II Rheumatoid Arthritis].30

Lymphotoxin

Produced exclusively by Th1 cells, lymphotoxin has many of the same biologic properties as TNF-α and utilizes the same cell receptor as TNF-α; it is also referred to as TNF-β. Like TNF-α, lymphotoxin lyses tumor cells but not normal cells, activates neutrophils, and increases vascular adhesion and extravasation of leukocytes. In addition, lymphotoxin plays a role in the development of lymphoid tissue.

Interleukin-1 and Interleukin-6

IL-1 is produced mainly by monocytes and macrophages but also by other cells, such as epithelial and endothelial cells. It is an endogenous pyrogen, and many of its functions are similar to those of TNF-α. It induces the production of additional IL-1 and of IL-6 from macrophages and induces glucocorticoid synthesis and the release of prostaglandin, collagenase, and acute-phase proteins. IL-1 increases the expression of surface molecules on endothelial cells, leading to adhesion of leukocytes and coagulation, and stimulates the production of macrophage chemokines that in turn activate neutrophils. IL-1 differs from TNF-α in that it does not produce necrosis of tumors or tissue injury, increase expression of MHC, or, by itself, mediate the Shwartzman reaction.

Macrophages produce an IL-1 receptor antagonist (IL-1ra) that, along with the IL-1 receptors shed from activated cells, inhibits IL-1 and thus acts as a regulator. Such natural inhibitors to IL-1 are now in clinical use to counteract certain inflammatory processes, especially in rheumatoid arthritis.

IL-6 is induced by IL-1 and by TNF-α from macrophages and, in turn, inhibits macrophage production of IL-1 and TNF-α. Like IL-1 and TNF-α, IL-6 is an endogenous pyrogen. IL-6 acts on hepatic cells to produce acute-phase proteins, such as fibrinogen, α2-macroglobulin, and serum amyloid A protein. This cytokine can also inhibit macrophage activation.

Interferon Gamma and Other Macrophage-Activating Factors

IFN-γ, produced by T cells and NK cells, is the primary macrophage-activating factor (MAF). MAFs play an important role in cell-mediated immunity because activated macrophages produce many cytokines and chemokines intimately involved in inflammation, including TNF-α, IL-1, IL-6, and MIF. Other MAFs include granulocyte-macrophage colony-stimulating factor (GM-CSF) and MIF. IL-1 and TNF-α have weak MAF activity. IL-12 stimulates NK cells to produce greater amounts of IFN-γ, enhancing IFN-γ-dependent reactions. Both on its own and by enhancing the effects of TNF-α, IFN-γ causes the expression of adhesion molecules on the surface of vascular endothelial cells, leading to T cell adhesion and extravasation.

The inflammatory effects of IFN-γ are countered by TGF-β and IL-10, which inhibit macrophage activation. IFN-γ has been used successfully to treat chronic granulomatous disease and drug-resistant visceral leishmaniasis.31

Migration Inhibitory Factor

MIF, the first T cell cytokine to be discovered, derives its name from the fact that it inhibits the random migration of macro phages in vitro. MIF acts as an endogenous hormone that counterregulates glucocorticoid action.32 Macrophages and T cells release MIF in response to glucocorticoids and other inflammatory stimuli. MIF then overrides the immunosuppressive effects of steroids on macrophage and T cell cytokine production.32,33

The gene for MIF is expressed in many different tissues.34 Large quantities of the gene are found in macrophages and pituitary cells. Indeed, LPS stimulates the release of MIF by the pituitary. When given to mice, MIF greatly enhances the lethality of LPS; conversely, anti-MIF antibodies completely reverse the lethality of LPS.35 MIF upregulates the receptor for LPS on macrophages (Toll-like receptor 4). Recombinant MIF activates macrophages to kill Leishmania and stimulates macrophages to produce TNF-α and nitric oxide. Mice lacking the gene for MIF show enhanced resistance to the lethal effects of high doses of LPS and Staphylococcus aureus enterotoxin B, as well as toPseudomonas aeruginosa and Escherichia coli, but they are susceptible to Leishmania, Salmonella, and Cysticercosis.36,37,38,39 MIF has been shown to play a pathogenic role in several experimental models of inflammation and autoimmunity, including glomerulonephritis, arthritis, inflammatory bowel disease, atherogenesis, and acute lung injury; it also inhibits p53 and enhances carcinogenesis. Mechanisms of MIF action include the activation of the extracellular signal-regulated kinase-1 and -2 (ERK-1 and -2), leading to activation of phospholipase A2, cyclooxygenase-2, and prostaglandin E2; enhancement of Toll-like receptor-4; and inhibition of p53 and apoptosis.

Anti-MIF therapies are under development. The goal is to increase the immunosuppressive and anti-inflammatory properties of endogenously released glucocorticoids, thereby reducing the need for steroid therapy in a variety of autoimmune and inflammatory conditions.32 Anti-MIF therapy should also have a role in treating some gram-negative infections and preventing septic shock.

Interleukin-5

IL-5 mainly affects eosinophil recruitment and activation. IL-5 is produced by Th2 cells and activated mast cells and stimulates the growth and differentiation of eosinophils. In addition to IL-5, other substances involved in the activation of eosinophils are TNF-α and an eosinophil cytotoxicity-enhancing factor derived from monocytes. Activated eosinophils produce tissue damage in allergic states and kill helminthic parasites.

Other Interleukins

DNA sequence information from the Human Genome Project has led to the identification of a number of new cytokines: IL-19 through IL-24. Their role in the immune response needs further exploration. Several of these cytokines appear to have some properties similar to those of IL-10, IL-12, and IL-15. Hematopoietic cytokines and growth factors are discussed elsewhere [see V:I Approach to Hematologic Disorders].

ANTI-INFLAMMATORY CYTOKINES

Interleukin-4 and Interleukin-13

IL-4 stimulates the expression of an adhesion molecule on endothelial cells, leading to the binding of eosinophils, lymphocytes, neutrophils, and monocytes and their subsequent extravasation. However, IL-4 also acts as an anti-inflammatory cytokine, inhibiting activated macrophages and diminishing the production of TNF-α and nitric oxide. IL-13 has the ability to take over some of the functions of IL-4. Both IL-4 and IL-13 induce IgE synthesis in B cells and differentiation of T cells to Th2 cells and can suppress inflammatory processes induced by Th1 cells. These cytokines also act on macrophages to suppress the inflammatory response. Activated mast cells and basophils produce additional IL-4. Of interest is that mutated IL-4 can inhibit IgE synthesis by IL-4 and IL-13 and may prove useful in treating some allergic states.

Transforming Growth Factor-b

TGF-β is produced by a variety of cells, including platelets, lymphocytes, activated macrophages, and placenta cells. It is an important anti-inflammatory cytokine because it inhibits the activation of macrophages and the maturation of cytotoxic T cells and thus controls the effects of many cytokines.

Interleukin-10

IL-10 is an important regulatory cytokine. It is produced by CD4+ and CD8+ T cells, B cells, macrophages, activated mast cells, and keratinocytes. Although usually associated with activity of Th2 cells, IL-10 can also be produced by Th1 cells. IL-10 suppresses lymphocyte responses by downregulating macrophage cytokines—including IL-1, TNF-α, IL-6, IL-8, GM-CSF, and granulocyte colony-stimulating factor (G-CSF)—and inhibiting nitric oxide production.

Chemokines

Chemokines are a superfamily of low-molecular-weight chemotactic cytokines that mediate the directional migration of leukocytes during normal and inflammatory processes.40 They play an important role in attracting granulocytes into sites of inflammation. There are four distinct families of chemokines, distinguished on the basis of the position of their first two conserved cysteine residues: CXC (the first two cysteines are separated by one amino acid), CC, C, and CX3C. The receptors for chemokines are all integral membrane G-protein-coupled receptors, which constitute one of the largest classes of signaling molecules.

CXC chemokines predominantly activate neutrophils.41 This family includes IL-8; β-thromboglobulin (β-TG); the growth-related gene products gro-α, gro-β, and gro-γ; and platelet factor 4. They are usually produced by monocytes, but some are produced by other cells, including T cells, endothelial cells, and platelets. IL-8 induces expression of neutrophil-binding integrins on endothelial cells, resulting in the rapid accumulation of neutrophils in tissues. The chemokine gro also stimulates neutrophil accumulation, as well as the release of lysosomal enzymes that contribute to the local inflammatory response. Platelet factor 4 and β-TG are released from aggregated platelets and stimulate fibroblasts, which are required for repair at sites of hemorrhage or thrombosis.

The CC chemokines activate T cells, monocytes, and eosinophils. This family includes RANTES (regulated on activation, normal T cell expressed and secreted), macrophage chemotactic and activating factor (MCAF), macrophage inflammatory protein-1α (MIP-1α), and MIP-1β. CC chemokines are produced by activated T cells and monocytes. RANTES is a potent attractant for memory T cells (but not for naive T cells) and also attracts monocytes. MCAF acts exclusively on monocytes, attracting them, activating them, and regulating the expression of integrins on their surface. MIP-1α and MIP-1β attract only monocytes. The CC chemokines eotaxin, eotaxin-2, and monocyte chemoattractant protein-4 (MCP-4) predominantly activate eosinophils.41

In addition to their role in inflammation, chemokines are important in the hemostasis of lymphocytes moving through the lymphatic system; in the location of T cells, B cells, and dendritic cells in the lymph node; in Th1 and Th2 cell development; and in angiogenesis, angiostasis, and metastasis of tumor. In fetal mice lacking the CXC chemokine receptor-4, the heart and cerebellum do not develop properly, indicating that chemokines also play a part in nonlymphoid organ development.42,43

Chemokine receptors play an important role as coreceptors for HIV. The virus first interacts with CD4 on T cells but requires a coreceptor to penetrate the cell membrane. The CC chemokine receptor-5 (CCR5), which mediates activation of T cells and macrophages, is the major coreceptor for some HIV-1 strains. The natural ligands for CCR5 include RANTES, MIP-1α, and MIP-1β.44 The CXC chemokine receptor-4 appears to be important in late-stage HIV infection.45

Effector Mechanisms in Cell-Mediated Immunity

Cell-mediated immunity encompasses the killing of invading microorganisms, such as bacteria, viruses, fungi, and parasites; the destruction of tumor cells; the rejection of tissue grafts; and injury to tissues in various disease states, including autoimmunity. Cell-mediated immune reactions can also be induced by contact with antigens, such as those found in poison ivy and numerous drugs. Drugs are more likely to provoke cell-mediated reactions when applied topically than when given systemically.

Most cell-mediated immune reactions involve initial interaction between sensitized T cells and antigens on presenting cells. This reaction can trigger several effector pathways, including activation of cytotoxic T cells, stimulation of T cell production of cytokines that activate macrophages and promote the proliferation of NK cells, and production of antibodies involved in antibody-dependent cell-mediated cytotoxicity by NK cells and other cell types. Although cell-mediated immune reactions other than antibody-dependent cell-mediated cytotoxicity do not require the presence of antibody or complement, they can be modified by these humoral factors. Subsequent events require cooperation between different subsets of T cells; the reactions involved are controlled by various cytokines.

The mechanisms of cell-mediated immunity involving T cell-macrophage interactions can be both protective (leading to the killing of invading microorganisms) and harmful (leading to inflammation and tissue destruction). Sometimes, the two go hand in hand; in tuberculosis, for example, both the killing of tubercle bacilli and the development of cavities in the lungs are consequences of T cell-macrophage interactions. In addition to the acquired cell-mediated immunity discussed above, innate immunity also involves the mounting of an immune response by cells directly stimulated by microorganisms. Macrophages, other granulocytic cells, and NK cells are involved in innate cell-mediated immune responses [see 6:II Innate Immunity].

CYTOTOXIC T CELLS

Cytotoxic T cells are antigen-specific effector cells that are important in resisting infectious agents, especially viruses that are present in cells other than macrophages; in killing tumors; and in allograft rejection. Most cytotoxic T cells are CD8+ T cells that recognize antigen presented by MHC class I molecules, although a considerable number of CD4+ T cells have the capability to kill target cells. Killing by a cytotoxic T cell begins with adhesion to the target cell (which requires magnesium ions), followed by the delivery of cytotoxic chemicals to the target cell (which requires calcium ions). The cytotoxic T cell then dissociates from the target cell; death proceeds in the absence of the cytotoxic T cell, which recycles to attack another target cell. If the cytotoxic T cell adheres to a cell that does not carry the targeted antigenic peptide-MHC molecule combination, no cytotoxic chemicals are released and the cells dissociate more rapidly.

Cytotoxic T cells develop granules that contain cytotoxic molecules, including perforins (proteins that produce holes or pores in a cell's surface membrane), serine proteases (granzyme A and granzyme B), and serine esterases.46 Of these, perforins are the most important, as has been shown in mice in which the gene encoding perforin has been deleted. A second killing mechanism involves the Fas ligand on the cytotoxic T cell and Fas on the target cell. Binding of these leads to apoptosis of the target cell. This is the only mechanism of killing available to mice that lack perforin, and it is used preferentially—but not exclusively—in CD4+ cytotoxic T cells [see Figure 5].

 

Figure 5. Cytotoxic Cells

Cytotoxic cells recognize surface markers on cells that are to be destroyed. (a) Apoptosis is triggered by the cytotoxic T cell through nonsecretory Fas-Fas ligand interaction. (b) Apoptosis is triggered by the cytotoxic T cell by means of secretory mechanisms initiated by perforin and granzymes.

Viral infection results in the production of a large number of virus-specific cytotoxic T cells. This is most dramatically shown during the initial responses to B cells infected with Epstein-Barr virus. Cytotoxic T cell clones specific for some antigen-MHC complexes are extremely abundant, constituting approximately 50% of all cytotoxic T cells.9 When the cytotoxic T cell response diminishes, these abundant T cell clones are probably removed through apoptotic mechanisms.

ACTIVATED MACROPHAGES

Macrophages are usually activated by Th1 cells that have been stimulated by antigens or microorganisms. Those Th1 cells then express CD40 ligand (CD40L) and produce macro phage-activating cytokines, especially IFN-γ and MIF. These cytokines, in combination with CD40L interacting with the CD40 on the macrophage surfaces, induces intracellular signaling transcription pathways in the macrophage. These path ways result in activation of transcription factors leading to production of various proteins and surface markers that characterize the activated macrophage. Activated macrophages produce reactive oxygen intermediates, including nitric oxide, that are involved in the destruction of microorganisms or foreign cells. Bacterial killing also involves phagolysosomal fusion, which mobilizes enzymes such as cathepsins.

Activated macrophages produce many of the inflammatory cytokines (e.g., IL-12, TNF-α, IL-1, and MIF) and chemokines (e.g., MIP-1) that are involved in immunity to microorganisms and foreign antigens and in enhancing the process of activation itself. Activated macrophages also express MHC class II and costimulatory molecules, which further amplify the process. In addition, activated macrophages produce the cytokines IL-10 and TGF-β; these counteract the activation, damping down the inflammatory process and acting as feedback regulators [see6:I Organs and Cells of the Immune System].

Acknowledgments

Figures 1 through 4 Dimitry Schidlovsky.

Figure 5 Seward Hung.

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