CHAPTER 84 FUNCTIONS OF T LYMPHOCYTES: T-CELL RECEPTORS FOR ANTIGEN
CHAPTER 84 FUNCTIONS OF T LYMPHOCYTES: T-CELL RECEPTORS FOR ANTIGEN
THOMAS J. KIPPS
T-Lymphocyte Antigen Receptors
The T-Cell Receptor for Antigen
Genetics of the T-Cell Receptor
Nature of T-Cell Receptor Antigen Recognition
Generation of T-Cell Receptor Diversity
The CD3 Complex
Function of the CD3 Complex
Molecular Features of the CD3 Complex
CD4 and CD8
Function of CD4 and CD8
Molecular Features of CD4 and CD8
Distribution of CD4 and CD8 on T-Cell Subsets
Immune Modulatory Molecules
All T cells express a receptor for antigen that is formed by two polymorphic polypeptides that invariably are associated with a collection of invariant proteins called CD3. The latter proteins are necessary for the surface expression and signaling by the T-cell receptor. The two polypeptides that form the T-cell receptor on most T cells are termed a and b; whereas a small subset of T cells have different polypeptides called g and d. The polypeptides of the T-cell receptor have a diversity that is comparable to that estimated for immunoglobulin molecules. However, unlike immunoglobulins, the T-cell receptors recognize small fragments of antigen, usually peptides, that are presented by major histocompatibility complex (MHC) molecules of another cell. As such, T-cell immune recognition generally requires cognate intercellular interactions between a T cell and another cell, sometimes called the antigen-presenting cell. The response of the T cell to antigen depends upon the intensity of the signal generated by ligation of the T-cell receptor. In addition, this signal is modified by the simultaneous ligation of other T-cell receptors for accessory molecules on the plasma membrane of the antigen-presenting cell. Because of this, the outcome of T-cell antigen recognition can range from immune activation and T-cell proliferation to specific T-cell tolerance and/or programmed cell death.
Acronyms and abbreviations that appear in this chapter include: APC, antigen-presenting cell; CTL, cytolytic T lymphocytes; DTH, delayed-type hypersensitivity; ER, endoplasmic reticulum; GM-CSF, granulocyte-macrophage colony stimulating factor; HIV, human immunodeficiency virus; ICAMs, intercellular adhesion molecules; IL-1, interleukin 1; ITAMs, immunoreceptor tyrosine-based activation motifs; LAG-3, lymphocyte activation gene 3; LFA, lymphocyte-function-associated; MHC, major histocompatibility complex; NK, natural killer; PI 3-kinase, phosphatidylinositol 3-kinase; TCR, T-cell receptor; TNF-b, tumor necrosis factor beta; V-like, variable-region-like; VLA, very late activation.
T-LYMPHOCYTE ANTIGEN RECEPTORS
THE T-CELL RECEPTOR FOR ANTIGEN
The receptor proteins of the T-cell antigen receptor are structurally related to immunoglobulin molecules (Fig. 84-1).1 The receptor for antigen on most T cells is formed by two polypeptides, termed a and b, that are linked to each other via disulfide bonds and associated with a collection of invariant proteins called CD3 (see Chap. 13).2,3 and 4 Following the rule of allelic exclusion, the T-cell receptor is clonally distributed, each T cell expressing a single a chain and a single b chain. Each chain has a hydrophobic leader sequence of 18 to 29 amino acids and an amino-terminal domain of 102 to 119 amino acids termed the variable region. This designation reflects the variation in the primary structure of these domains among different T-cell receptor polypeptides. Furthermore, each chain has a carboxyl-terminal region segment of 87 to 113 amino acids, termed the constant region because this region is invariant among chains of the same class. Owing to their role as surface-membrane receptors, each chain also has a small connecting peptide, a transmembrane region of 20 to 24 amino acids, and a small cytoplasmic region of 5 to 12 residues at the carboxyl terminus.
FIGURE 84-1 Schematic diagram of the T-cell receptor (TCR) molecules. Each chain of the TCR is labeled on the far right side of the diagram. TCR-a and TCR-b together form the TCR-ab heterodimer. Similarly, TCR-d and TCR-g form the dg heterodimer. Lines with S indicate either inter- or intrachain disulfide bridges. Domains of each chain are marked by letters: L, leader peptide; V, variable region; D, diversity segment; J, joining segment; C, constant region; H, hinge region; TM, transmembrane region; CY, cytoplasmic domain.
Like the immunoglobulin domains, the variable and constant regions each contain cysteine residues at positions consistent with the presence of a centrally located disulfide loop of 63 to 69 amino acids. Sequence comparisons indicate that several amino acids that are highly conserved in immunoglobulins, including those involved in domain-domain interactions, also are conserved in the T-cell receptor chains. Furthermore, algorithms that predict a given amino acid primary sequence’s hydropathicity, hydrophobicity, and potential for formation of b-pleated sheets and a helices suggest that the T-cell receptor chains fold into very similar tertiary configurations, as do the light and heavy chains of the immunoglobulin molecule. The structural and primary sequence similarities of the T-cell receptor justifiably place the genes encoding these receptor proteins in the so-called immunoglobulin supergene family.5
Over 90 percent of mature T cells express an ab heterodimer, making this the major class of T-cell receptor.2,3 and 4 Each molecule is composed of a single acidic a glycoprotein of 39 to 46 kDa linked to a more basic 40- to 44-kDa b glycoprotein via a disulfide bond between the constant regions of the two chains (Fig. 84-1). Within minutes after being translated into protein, both chains are glycosylated and assembled into a heterodimer for subsequent expression on the cell surface. The a- and b-chain genes each contain at least three sites for N-linked glycosylation. In addition, the b chain contains simple high-mannose glycan side chains. The maximum size of the deglycosylated cell surface forms of the a and b subunits are 27 kDa and 32 kDa respectively.
Less than 10 percent of blood T cells and thymocytes exclusively express a different T-cell receptor heterodimer composed of two glycoproteins designated g and d (Fig. 84-1).6 The development of gd-expressing T cells appears distinct from that of ab-expressing T cells.7,8 In fact, T cells bearing gd receptors apparently constitute a distinct cell lineage that can undergo relative expansion in response to infection with certain organisms, such as Listeria monocytogenes.9 In secondary lymphoid tissues (see Chap. 5), only about 1 to 5 percent of the CD3-positive cells express gd receptors. However, in epithelial tissues most T cells express gd receptors, especially in the epidermis and small intestine of the mouse.
The amino acid sequence of the g chain is more like that of the T-cell receptor b chain, while the amino acid sequence of the d chain is more like that of the a chain. Like the ab heterodimer and immunoglobulins, the gd heterodimer is clonally distributed. Like the homologous ab heterodimer, the gd heterodimer also is associated with the CD3 complex and appears capable of stimulating T-cell activation when bound to specific ligand. Together these two chains have structural and size characteristics similar to those of the ab heterodimer. However, the tertiary structure of variable regions of gd T-cell receptors has a closer resemblance to immunoglobulin variable regions than to the variable regions of ab T-cell receptors.
GENETICS OF THE T-CELL RECEPTOR
Similar to the immunoglobulin genes, each chain of the T-cell receptors is encoded by discrete genetic elements that rearrange during development (Fig. 84-2) (see Chap. 83). Evaluation for T-cell receptor gene rearrangements can distinguish between patients who have clonal T-cell lymphoproliferative diseases from those who have nonneoplastic polyclonal T-cell expansion.10 Furthermore, molecular analysis for clonal T-cell receptor gene rearrangements can be used to detect minimal residual disease in patients treated for clonal T-cell disorders.11
FIGURE 84-2 Schematic diagram of possible rearrangements of the TCR-b-chain genes. The TCR-b-chain genes in the germ-line DNA configuration are depicted in the middle. Possible recombination of either the first constant region (C1, above) or the second constant region (C2, below) with the variable region (V), diversity (D), or joining (J) segments are indicated by the lines.
Located at band q35 on the long arm of chromosome 7, the b-chain complex has two closely linked genes, each capable of encoding the b-chain constant region. Each constant region gene is associated with a cluster of functional Jb-gene segments and a single Db segment. The functional gene encoding the variable region of the b chain is constructed from the rearrangement of any of about 50 variable region gene segments to either one of the two Db regions and one of 13 Jb regions. The a-chain complex is located at band q11.2 on the long arm of chromosome 14 and thus is linked to the immunoglobulin heavy-chain complex. The a-chain gene complex consists of one constant region gene and at least 50 different variable region gene segments. The functional gene encoding the a-chain variable region is derived from the juxtaposition of any one of the variable region gene segments with one of the many Ja segments through rearrangement that generally involves the deletion of the intervening DNA.
The organization of the g and d genes is similar to that of the a and b genes except for some significant differences. First, the gene complex encoding the d genes is located entirely within the a-chain gene complex between the Va and Ja gene segments.12 Consequently, any rearrangement of the a-chain genes inactivates the genes encoding the d chain. Second, there are many fewer V gene segments in the g and d gene complexes than at either the T-cell receptor a or a gene loci. The g-gene complex on band p15 on the short arm of chromosome 7, for example, has only about 12 Vg gene segments, two virtually identical Jg segments, and two constant region gene segments.13 Moreover, there are only about four Vd gene segments, three Dd gene segments, three Jd gene segments, and a single constant region gene in the d gene complex. Consequently, most of the variability in the g and d chains is found in the junctional region formed during the process of gd T-cell receptor gene rearrangement. The amino acids encoded by this region lie at the center of the T-cell receptor binding site.
NATURE OF T-CELL RECEPTOR ANTIGEN RECOGNITION
Although highly similar in structure, there are important differences in the ways that T-cell receptors and immunoglobulins recognize antigen.1 Whereas immunoglobulins can bind antigens directly, T-cell receptors generally recognize peptide antigens that are bound to a molecule of the MHC on the surface of another cell.
There are two basic classes of MHC molecules. Class I MHC molecules bind peptides that generally are derived from proteins synthesized and degraded in the cytosol. The human histocompatibility antigens HLA-A, -B, or -C are class I molecules. Class II MHC molecules, such as the HLA-D antigens DP, DQ, and DR, generally bind peptides that are derived from exogenous proteins that are degraded in the cellular vesicles. Peptides that bind to MHC class I molecules are usually 8 to 10 amino acids long. The binding of such peptides is stabilized by contacts between atoms in the free amino and carboxyl termini of the peptide and the peptide-binding groove of all MHC class I molecules. Peptides that bind to MHC class II molecules, on the other hand, are at least 13 amino acids long and can be much longer, although they generally are trimmed by peptidases to be 13 to 17 amino acids in most cases. This is because MHC class II molecules do not bind the two ends of the peptide such as the MHC class I molecules.
Nevertheless, for either class I or class II molecules, there exists a discrete binding site for the peptide that lies in a cleft between two a helices of the MHC molecule. Steric factors, hydrogen bonding, and hydrophobic interactions between the peptide and the particular MHC molecule serve to tether the peptide within this cleft, thus generating a tertiary structure that is formed by amino acid residues of both the MHC and the peptide antigen. It is this tertiary structure that is recognized by the T-cell receptor for antigen.
There are several genes for each class of MHC molecule, and each of these is highly polymorphic with many different alleles (see Chap. 138). The particular combination of MHC alleles found on an individual chromosome is known as a MHC haplotype. Both maternal and paternal MHC haplotypes are expressed concomitantly. Polymorphism in the MHC molecules primarily affects the amino acids lining the clefts that cradle the peptide antigen.
Each allele encodes a MHC molecule that can bind a restricted set of peptides with a discrete sequence motif. Moreover, different alleles of the same MHC molecule will bind peptides with different sequence motifs. This polymorphism combined with biallelic expression of MHC genes and the degeneracy of MHC molecules on any given MHC haplotype ensure that a wide variety of different peptides can be presented to the T cell for immune recognition. However, because T cells actually interact with a tertiary structure that is largely dictated by a particular MHC molecule, T cells manifest MHC-restricted antigen recognition. In other words, a given T cell is specific for one peptide bound to one MHC molecule.
Some T cells, however, do not recognize peptide bound to a given MHC molecule. Such T cells recognize nonpeptide antigens that are presented by MHC class-I-like molecules encoded by genes that map outside the MHC region. One such family of molecules, called CD1, first defined as a cell-surface differentiation antigen (see Chap. 13) subsequently was found to present nonpeptide antigens to T cells.4 For example, in cells infected with mycobacteria, the CD1 molecules are able to bind and present the mycobacterial membrane components such as lipoarabinomannan or mycolic acid. T cells that recognize these complexes play an important role in the immune response to Mycobacterium tuberculosis.
Most gd-expressing T cells may not be restricted by polymorphic self-molecules of the MHC.15 Furthermore, gd receptors bind different ligands than the ab T-cell receptors. Some gd T cells recognize products of certain MHC class IB genes, or variants of the standard MHC class I genes that have little polymorphism (see Chap. 138). Other gd receptors apparently recognize antigen directly like immunoglobulin molecules.
GENERATION OF T-CELL RECEPTOR DIVERSITY
Diversity of the T-cell receptor for antigen is achieved by several mechanisms, some of which are the same as those that generate diversity among immunoglobulin molecules16 (see Chap. 83). The joining of different V, D, and J elements to produce a complete V gene, the presence of uncorrected errors made during the recombination of these genetic elements, and the combinatorial diversity afforded by the random pairing of two chains encoded by separated gene complexes all function to enhance the diversity of the T-cell antigen receptor repertoire.17,18 An important difference between T cells and B cells in how they may enhance receptor diversity, however, is that B cells are capable of somatic mutation (see Chap. 83). This process apparently occurs uniquely in immunoglobulin genes that have undergone rearrangement and does not operate on the variable region genes of the T-cell receptor.
That T-cell receptor genes do not undergo somatic mutation probably relates to the central role that T cells have in directing host immune defenses. During differentiation, immature precursors to ab-expressing T cells pass through the thymus, where they are “educated” to distinguish self from nonself vis-a-vis the cell-surface proteins of the major histocompatibility complex (see Chap. 5 and Chap. 82). Because the ligand for the ab T-cell receptor is “processed” antigen presented by the proteins of the MHC,19,20 close interaction with the molecules of the MHC might be lost if the variable region genes of the T-cell receptor were allowed to diverge significantly from the inherited germ-line repertoire. Furthermore, somatic mutation of expressed T-cell receptor variable region genes may lead to constitutive T-cell activation to processed self-antigen presented by self-MHC molecules, this perhaps leading to autoimmune disease.
THE CD3 COMPLEX
FUNCTION OF THE CD3 COMPLEX
Closely associated with and required for the surface expression of the two polypeptides of the T-cell receptor is the CD3 complex of polypeptides (see Chap. 13). The CD3 polypeptides also are responsible for signal transduction from the T-cell receptor heterodimer to intracellular plasma membrane-associated proteins.21 Upon binding to specific ligand, the T-cell receptor ab (or gd) heterodimer undergoes steric changes that result in the phosphorylation of the intracellular domains of several polypeptide chains in the CD3 complex. Together, these perturbations of the ab/CD3 complex result in T-cell activation through a cascade of biochemical events22 (see Chap. 15). As such, the CD3 surface proteins are integral components of the functional T-cell receptor complex.23
The CD3 complex is composed of at least four distinct chains that are designated CD3g, CD3d, CD3e, and CD3z (see Chap. 13). The CD3g and CD3d chains are not to be confused with the g:d chains of the T-cell receptor. Rather, the CD3g, CD3d, and CD3e chains each form a tight association with the a:b (or g:d) receptor heterodimer on the T-cell surface (Fig. 84-3). Each has a negatively charged amino acid in the central portion of the hydrophobic transmembrane region that stabilizes the CD3 complex with the two chains of the T-cell receptor. The CD3e chain couples with either the CD3g or the CD3d chain. The CD3z chain, on the other hand, forms a disulfide-like homodimer that only weakly associates with the CD3 complex and cannot be coimmunoprecipitated readily with antibodies to the T-cell receptor or other CD3 polypeptides. Very little of the CD3z chain is present on the T-cell surface (Fig. 84-3). However, the CD3z chain is required for directing the T-cell receptor complex to the cell surface and for receptor-mediated signal transduction,24 and mice made deficient for expression of the CD3z chain have impaired T-cell development.25 In mice, the CD3z chain infrequently may form a disulfide-linked heterodimer with another polypeptide chain, designated CD3h. CD3h actually is generated through alternate RNA splicing of the gene encoding the CD3z chain. However, there does not appear to be a CD3h protein in humans.26
FIGURE 84-3 Schematic diagram of the T-cell interactions with an antigen-presenting cell. The thick gray lines depict the plasma membranes of the interacting cells. The molecules of the antigen-presenting cell, namely LFA-1, ICAM-1 or ICAM-3, LFA-3, MHC class II, and CD80 or CD86, are displayed on top, while the T-cell antigens, ICAM-2, LFA-1, CD2, CD4, the T-cell receptor complex (TCR complex), and CD28, are shown on the bottom of the diagram. Thin lines connecting the stick figures indicate disulfide bridges. The TCR complex consists of the ab heterodimer that is noncovalently coupled with the d, e, g, and z chains of CD3, as indicated. This complex can recognize peptide antigen (designated by the diamond labeled P) that is cradled by the a and b chains of the MHC class II molecule of the antigen-presenting cell. The avidity of this interaction is enhanced by CD4 on the T-cell surface that interacts with nonpolymorphic determinants on the MHC class II molecule. The interaction steps between the T cell and the antigen-presenting cell are listed at the bottom of the figure. T-cell molecules ICAM-2 (CD102), LFA-1 (CD11a/CD18), and CD2 bind to LFA-1, ICAM-1 (CD54) or ICAM-3 (CD50), or LFA-3 (CD58) respectively that are present on the surface of the antigen-presenting cell. These molecules provide for better adhesion between the T cell and the antigen-presenting cell (adhesion), allowing for time for the TCR receptor complex to find the MHC molecule bearing a specific peptide antigen (antigen recognition). Should the antigen-presenting cell express CD80 or CD86, then simultaneous ligation of CD28 will occur (costimulation), leading to activation of the reactive T cell.
MOLECULAR FEATURES OF THE CD3 COMPLEX
The genes encoding CD3g, CD3d, or CD3e chains are clustered in band q23 on the long arm of chromosome 11. CD3g has a 16-kDa polypeptide backbone that is heavily glycosylated to assume a final molecular mass of 25 to 28 kDa. CD3d and CD3e are each 20 kDa in molecular mass. The CD3d is a glycoprotein consisting of 30 percent carbohydrate. In contrast, CD3e is not glycosylated. CD3d and CD3g are highly homologous at both the protein and nucleic acid sequence level. The nucleic acid sequence of each predicts CD3d and CD3g to have typical signal peptides, respective hydrophilic extracellular domains of 79 to 89 amino acids, hydrophobic transmembrane regions of 27 amino acids, and hydrophilic intracellular domains of 44 to 55 amino acids. CD3e is similar, with a 22-residue signal peptide, an extracellular domain of 104 amino acids, a transmembrane domain, and a comparatively long intracellular domain of 81 amino acids. The CD3z chain, on the other hand, has no sequence or structural homology to the other three CD3 chains. It is a nonglycosylated protein of 16 kDa in molecular mass that is encoded by a gene found on chromosome 1. The CD3z chain has only a very short extracellular domain of 6 to 9 amino acids, a transmembrane domain of 21 amino acids, and a long intracellular domain of 113 amino acids. None of the CD3 polypeptides bear significant homology to immunoglobulins, indicating that the genes encoding the chains of the CD3 complex do not belong to the immunoglobulin supergene family. In addition, there is no variability in the extracellular domains of the CD3 proteins, making it unlikely that these molecules contribute to the specificity of antigen recognition.
Also considered a CD3 polypeptide is CD3w. This polypeptide is an intracellular protein that transiently associates with the CD3-T-cell receptor complex during its assembly in the endoplasmic reticulum (ER).27 However, CD3w dissociates from the CD3 complex in the ER and does not travel to the plasma membrane. As such, CD3w plays a role in the intracellular assembly and transport of the intact CD3/T-cell receptor complex.
The cytoplasmic domains of all the CD3 proteins contain sequences called immunoreceptor tyrosine-based activation motifs (ITAMs). These sequences allow the CD3 proteins to associate with cytosolic protein tyrosine kinases following receptor ligation, thus transducing a signal to the interior of the T cell (see Chap. 15). The cytoplasmic domains of CD3e and CD3z are particularly important in this regard.
CD4 AND CD8
FUNCTION OF CD4 AND CD8
CD4 and CD8 facilitate T-cell antigen recognition by interacting with the glycoproteins of the major histocompatibility complex.28 Moreover, during antigen recognition, CD4 and CD8 molecules associate on the plasma membrane with components of the T-cell receptor for antigens. For these reasons, these molecules are considered coreceptors of the T-cell receptor for antigen.
The CD8 molecule binds to nonpolymorphic regions of the MHC class I molecule (HLA A, B, or C), and the CD4 molecule binds to nonpolymorphic regions of the MHC class II molecule (HLA-D region-encoded molecules: DP, DQ, and DR). CD8 or CD4 enhance by over 100-fold the adhesion between the T cell’s CD3/T-cell receptor complex and the MHC glycoproteins expressed by an antigen-presenting cell (APC) or target cell. These molecules apparently focus MHC molecules of the APC or target cell onto the T-cell surface, allowing for specific recognition of “processed” antigen that is cradled within the MHC glycoproteins. Because CD4 and CD8 differ in their MHC-binding specificities, T cells expressing CD4 or CD8 generally recognize antigens presented by class II or class I MHC glycoproteins respectively.29 This selectivity is underscored by studies on transgenic mice that lack expression of MHC class II molecules. Such animals fail to develop mature CD4 T cells, owing to their inability to select for such cells in the thymus.30 In addition, CD4 or CD8 molecules also may enhance antigen responsiveness by transducing a signal either directly or in concert with CD3/T-cell receptor complex.31
MOLECULAR FEATURES OF CD4 AND CD8
CD4 and CD8 are glycoproteins that share structural features with other receptor molecules encoded by genes within the immunoglobulin supergene family. CD8 is expressed as a heterodimer of CD8a and CD8b or as a CD8a homodimer. Each chain contains a single immunoglobulin-like domain linked to the membrane by a segment of polypeptide chain that could have an extended conformation. These chains are encoded by genes that are linked closely to the immunoglobulin k light-chain locus at band p12, on the short arm of chromosome 2. The protein sequence of the amino-terminal domains of each CD8 chain shares greater than 28 percent homology with k light-chain variable regions. As such, these domains are called the variable-region-like (V-like) domains. Following this V-like domain, the CD8 molecule has a short region rich in prolines, threonines, and serines that resembles the immunoglobulin hinge region. This region also contains sites for O-linked glycosylation. A hydrophobic transmembrane region anchors this hinge-like region. The CD8 molecule has a 28-amino acid cytoplasmic tail consisting of basic residues. Two cysteines within the V-like domain form a disulfide bridge that stabilizes the immunoglobulin-like fold. An additional cysteine residue is located each within the V-like domain, the hinge region, the transmembrane, and cytoplasmic segments. These cysteines form intermolecular disulfide bridges between two or more CD8 molecules; these bridges stabilizing the CD8 homodimers and multimers that are expressed on the T-cell surface. The cell-surface CD8 homodimer shares the same approximate geometry as heavy- and light-chain immunoglobulin heterodimers.
CD4, on the other hand, does not form such homodimers. It is a 55-kDa monomeric glycoprotein that is encoded by a gene that maps to the short arm of chromosome 12. It consists of five external domains, a stretch of hydrophobic transmembrane residues, and cytoplasmic tail of 40 residues. Similar to CD8, the amino-terminal domain of CD4 also has extensive homology to immunoglobulin light-chain variable regions. However, following this V-like domain is a domain of 270 amino acids that bears little resemblance to other proteins encoded by genes of the immunoglobulin supergene family. Together with this 270-amino acid domain, the V-like domain of the CD4 molecule forms an intramolecular heterodimer on the T-cell surface.
The cytoplasmic regions of CD4 and CD8 are conserved among vertebrates, suggesting that these regions are essential for the function of these molecules. The cytoplasmic region of CD4 contains five serines and threonines, one or more of which is phosphorylated by protein kinase C upon activation of T cells by phorbol esters or exposure to antigen. Subsequent to phosphorylation, the CD4 glycoprotein is internalized concomitant with T-cell activation. Similarly, the CD8 protein also possesses a highly charged and conserved cytoplasmic domain that may be involved in transmembrane signal transduction. In this light, CD4 and CD8 actually may be integral components of the functional T-cell receptor complex required to trigger T-cell activation and/or function upon exposure to specific antigen.
CD4 also is a coreceptor molecule for the human immunodeficiency virus (HIV).32,33 Binding of CD4 along with a chemokine receptor facilitates entry of the virus into those T cells that are stimulated specifically in an antigen-driven immune response. Monoclonal antibodies specific for the CD4 glycoprotein can block infection by HIV. Moreover, genetically engineered soluble CD4 can compete with cell-surface CD4 for HIV binding. Finally, disease progression in patients infected with HIV correlates with depletion of blood T cells that express CD4 (see Chap. 89).
DISTRIBUTION OF CD4 AND CD8 ON T-CELL SUBSETS
CD4 and CD8 are expressed by nearly all T-cell precursors. Only a fraction of thymocytes express neither CD4 nor CD8. These cells are thought to be the marrow-derived precursors to the vast majority of thymocytes that express both CD4 and CD8. More mature thymocytes and all peripheral T cells express either CD4 or CD8, but not both.
HELPER AND SUPPRESSOR (CYTOLYTIC) T CELLS
The mutually exclusive expression of CD4 or CD8 defines two major blood T-cell subsets. Blood T cells that express CD8 are designated suppressor T cells. These cells normally constitute 25 to 35 percent of the peripheral T-cell population. Suppressor T cells more appropriately should be designated cytolytic T lymphocytes (CTL), in that a main function of these cells is to lyse cells, termed target cells, which bear surface antigens for which they are specific. Blood T cells that solely express the CD4 surface antigen are designated helper T cells. These cells normally comprise 65 percent of the blood T cells. Generally, helper T cells produce lymphokines upon activation by foreign antigens presented by MHC molecules expressed on the surface of APCs.
CD4+ T-CELL SUBSETS
Mature CD4+ T cells may be divided into at least two subsets, each able to elaborate a distinctive profile of cytokines upon activation.34,35 The primary differences are that TH1 cells are the major helper T-cell source of interleukin 2 (IL-2), interferon gamma (IFN-g), and tumor necrosis factor beta (TNF-b), while TH2 cells are the predominate producers of IL-4 and IL-5 (Table 84-1). In addition, TH1 cells may be the major helper T-cell source of tumor necrosis factor alpha (TNF-a) and granulocyte-macrophage colony stimulating factor (GM-CSF), while TH2 cells apparently are the major T-cell producers of IL-10 and IL-13. A third cell subset, designated TH0, is comprised of CD4+ helper T cells that may elaborate all of these cytokines and may represent a precursor population to the other two subsets.
TABLE 84-1 MAJOR CD4+ T-CELL SUBSETS
These CD4+ T-cell subsets may be distinguished by their differential expression of certain surface molecules. Human TH1 cells preferentially express CD26, membrane IFN-g, and the chemokine receptors CCR5 and CXCR3.36 Moreover, TH1 cells apparently express higher levels of the lymphocyte activation gene 3 (LAG-3), a ligand for major histocompatibility complex class II antigens that is structurally related to CD4.37 TH2 cells, on the other hand, preferentially express CD62L, CD30, and the chemokine receptors CCR3, CCR4, CCR8, and, to some extent, CXCR4.36,38,39 Differences in the expression levels of these chemokine receptors may account for the differences in the tissue-specific migration of these helper T-cell subsets.40
Each of these two T-cell subsets has a discrete function.41 TH1 cells activate the microbicidal properties of macrophages and induce B cells to make IgG antibodies that are very effective at opsonizing extracelllar pathogens for uptake by phagocytic cells. In addition, TH1 cells are the major helper T cells involved in delayed-type hypersensitivity (DTH). The cytokines elaborated by TH1 cells stimulate macrophage Fc receptor expression, phagocytosis, and antigen presentation, enhancing the capacity of macrophages to kill intracellular pathogens. TH2 cells, on the other hand, initiate the antibody response to antigen by activating naive antigen-specific B cells to produce IgM antibodies and subsequently stimulate the production of different isotypes, including IgA and IgE and neutralizing and/or weakly opsonizing subtypes of IgG.
Extracellular antigens tend to stimulate the generation of TH2 cells, whereas pathogens that accumulate in large numbers inside macrophage vesicles tend to stimulate differentiation of TH1 cells.42 Immune responses restricted to that of TH1 cells have been observed in patients with leprosy who have developed cellular immunity to Mycobacterium leprae43 or in patients with arthritis triggered by infection with either Borrelia burgdorferi (Lyme disease)44 or Yersinia enterocolitica.45 The cytokines made by TH2 cells, on the other hand, facilitate production of IgE antibodies and stimulate mast cells and eosinophils. While these effects may contribute to development of allergy, 46,47 these responses also may be protective in helminth infections.48,49 Studies demonstrate that eosinophilia and elevated IgE that accompany infection with Schistosoma mansoni, for example, are due to the induction of TH2-type cells in the immune response to parasite ova.50,51 In addition, because they express IL-4, TH2 cells appear better suited to induce B-cell responses to antigen.
MEMORY T CELLS
Following a successful immune response to antigen, antigen-specific T lymphocytes may differentiate into memory T cells.52,53 and 54 These cells may have less stringent requirements for activation and an enhanced capacity for lymphokine production upon rechallenge with the same antigen.55 Alternatively, these cells may develop an impaired responsiveness to antigen when stimulated in the absence of certain costimulatory factors, thus rendering these cells “anergic”56 (see Chap. 15). In any case, naive and memory CD4+ or CD8+ T lymphocytes apparently differ in surface phenotypes, response to recall antigens, rate of cycling, and migration.57,58 These subsets may be distinguished using antibodies specific for isoforms of CD45.59,60
CD45, also known as leukocyte common antigen or T200, consists of a family of membrane glycoproteins, ranging from 180 to 220 kDa, that are expressed on all leukocytes. Each member is the product of a single complex gene on chromosome 1 that contains 34 exons. Exons 3 through 7 may be spliced differently at the RNA transcript level to generate several distinct mRNA and protein products. The deduced amino acid sequences of these protein products have extracellular domains ranging from 391 to 552 amino acids, a transmembrane region, and a highly conserved cytoplasmic domain of 705 amino acids. This large cytoplasmic domain contains an intrinsic tyrosine phosphatase activity that is important in the regulation of various activation pathways involving tyrosine kinase activity, such as those involved in signal transduction via the T-cell receptor for antigen. 61,62 and 63 (See Chap. 15)
Differential glycosylation of the CD45 peptide backbone contributes further to the heterogeneity of the members of this family of proteins. Different isoforms of CD45 have distinct patterns of expression during lymphocyte ontogeny and activation.64 Monoclonal antibodies have been developed that recognize individual members of this family that are expressed on physiologically distinct lymphocyte subsets (see Chap. 13). Isoforms of CD45 that are expressed on such distinct subsets of cells are designated as CD45R.
Naive CD4+ T cells express a form of CD45R, called CD45RA, whereas memory CD4+ T cells and CD8+ T cells express another isoform of CD45R, designated CD45RO. These isoforms can be recognized by monoclonal antibodies 2H4 and UCHL1 respectively.65 Evaluation for the expression level of another isoform of CD45, designated CD45RB, also can be useful for distinguishing memory T cells. Within the CD4+ memory T-cell population, for example, there is an increase of helper activity associated with the shift from a CD45RBbright to a CD45RBdim phenotype.66 In addition, relative to naive T cells, memory T cells also express lower levels of L-selectin (CD62L) and higher levels of CD29 and CD4453 (see Chap. 13). It is still uncertain whether the differentiation of CD4+ T cells with the “naive” phenotype (i.e., CD4+CD45RA+CD29lowCD44low) to cells having the “memory” phenotype (i.e., CD4+CD45RO+CD29highCD44high) is irreversible,65 and whether these phenotypic changes are valid for all TH1- and TH2-type CD4+ T cells.67
IMMUNE MODULATORY MOLECULES
CD28 is a 44-kDa disulfide-linked homodimer that is expressed on most resting T cells and plasma cells.68,69 Mature thymocytes have higher levels of CD28 than the immature cells. Among peripheral T cells, nearly all CD4+ and approximately 50 percent of CD8 T cells are positive. In general, activation of T cells induces enhanced expression of CD28, but ligation of CD28 leads to its transient downregulation.69
CD28 is another member of the immunoglobulin superfamily that is an important receptor for CD80 and CD86. It binds to both CD80 and CD86 using a highly conserved motif (MYPPPY) in a loop that resembles the third complementarity-determining region of immunoglobulin molecules.70 CD28 binds to CD80 with relatively low affinity (Kd = 4 µM) and dissociates very rapidly (–Koff=1.6 s–1).71 Its binding to CD86 may be even weaker.72
CD28 is one of the major costimulatory molecules that is important in T-cell activation.73 Ligation of CD28 by CD80 or CD86, or by anti-CD28 antibodies, serves as an important cosignal to T-cell receptor cross-linking.68,74,75,76 and 77 The cytoplasmic domain of CD28 interacts with phosphatidylinositol 3-kinase (PI 3-kinase), the complex between GRB-2 and the guanine nucleotide exchange protein SOS (GRB-2/SOS), and the tyrosine kinase ITK.78 The SH2 domains in PI 3-kinase and GRB-2/SOS mediate binding to the CD28 motif YMNMT, after it has been phosphorylated by Lck and Fyn following ligation of CD28 79,80 (see Chap. 15). Ligation of CD28 thereby activates several signal-transduction pathways.81 This cosignal enhances the transcription of interleukin-2 and the stability of interleukin-2 transcripts, thereby stimulating the growth of naive T cells.82 Although mice lacking CD28 can mount effective T-cell responses, they are defective in T-cell-dependent antibody responses, suggesting that CD28 is necessary for T-cell « B-cell interactions and the development of antibody responses to antigen.83
The requirement for the same cell to present both the specific antigen and the costimulatory signal plays an important role in preventing destructive autoimmune responses to self-tissues.84 The initiation of T-cell responses requires simultaneous ligation of the T-cell receptor and CD28. This restricts the initiation of T-cell responses to antigen-presenting cells that express both the peptide antigen in the context of self-MHC molecules and the ligands for CD28, namely CD80 and CD86. This is important, as not all self-reactive T cells undergo deletion in the thymus because not all self-peptides are presented in the thymus (see Chap. 5). This is especially true for specialized tissues that express proteins that are never expressed in the thymus. If simultaneous ligation of the T-cell receptor and CD28 was not required, then T cells that recognize the self-peptide expressed by the MHC of such specialized tissues could become activated, leading to autoimmune rejection of the specialized tissue. Instead, ligation of the T-cell receptor in the absence of CD28-ligation leads to a state of anergy, in which the T cell expressing that receptor becomes refractory to activation.68,85 Anergic T cells are unable to produce interleukin-2 following ligation of their antigen receptors. This prevents these T cells from proliferating and differentiating into effector cells when they encounter antigen. This is an important basis for development of peripheral tolerance for self-antigens that are not expressed in the thymus (see Chap. 5 and Chap. 82).
CTLA-4 (CD152) is another receptor for CD80 and CD86. It is a 50-kDa disulfide-linked homodimer that shares 31 percent identity with CD28. The gene encoding this receptor is closely linked with that encoding CD28 on the long arm of chromosome 2 at 2q33-q34. However, in contrast to the constitutive expression of CD28, T cells express CD152 only upon activation. Expression of CD152 peaks at approximately 24 h after activation and then subsides by 72 h but is always about 30- to 50-fold lower than that of CD28. Ligation of CD28 is particularly effective in inducing CD152.
CD152 binds to CD80 and CD86 approximately 20 times more avidly than CD28, with Kds of 0.4 and 2.2 µM respectively.71,72 Ligation of CD152 transduces a negative signal to the activated T cell, thereby making it less sensitive to stimulation by the antigen-presenting cell.76,86 Anti-CD152 antibodies can enhance T-cell responses in vitro and in vivo.87,88 Mice made genetically deficient in CD152 develop a fatal disorder that is characterized by massive lymphocyte proliferation,89,90 indicating that CD152 serves as an important brake on runaway T-cell activation.
Besides the CD3/T-cell receptor molecules and CD4 or CD8, several other surface proteins are required for efficient T-cell antigen recognition.91 Some of these surface proteins may be termed adhesion molecules, in that they facilitate the adhesion of the T cell to its appropriate antigen-presenting cell or target cell (see Fig. 84-3).92 By facilitating cell adhesion, these accessory molecules permit the T-cell antigen receptor complex to interact better with the MHC glycoproteins of the other cell, allowing for efficient T-cell antigen recognition and activation. Because each member of this group of accessory molecules has distinctive affinities for the surface molecules expressed by the APC or target cell, differential expression of the accessory molecules may pattern differences in the antigenic specificities and/or cell types with which a given T cell best may interact. As such, the differential expression of these accessory molecules by peripheral T cells may define physiologically distinct T-cell subsets. Other accessory molecules involved in T-cell activation, function, and/or signal transduction are discussed in Chap. 15
The lymphocyte-function-associated (LFA) molecules are an important family of glycoproteins that facilitate efficient cell-cell adhesion.93,94 The molecules were first identified with monoclonal antibodies that could block T-cell function, such as cytotoxic T-cell-mediated killing of target cells. From these early experiments three major surface molecules were identified and designated LFA-1, LFA-2, and LFA-3. Following international convention, LFA-2 will be referred to as CD2.
LFA-1 belongs to a family of three related glycoproteins: LFA-1, MAC-1, and p150,95 (see Chap. 13). These proteins also are called “integrins” because they are hypothesized to coordinate the binding of cells to other cell types and to extracellular proteins.95 Each protein consists of a distinct a subunit noncovalently associated with the common b2 subunit glycoprotein of 95 kDa, designated as CD18. Because they share a common b2 subunit, these molecules also are referred to as the b2-integrins. The a subunit of LFA-1, designated CD11a, is a 180-kDa glycoprotein (see Chap. 13). Coupled together with the common b2 subunit, this 180-kDa molecule is expressed on over one-third of all marrow cells, all T cells, B cells, and natural killer (NK) cells. The a subunit of MAC-1 is a glycoprotein of 170 kDa, designated CD11b. MAC-1 is expressed on NK cells, monocytes, macrophages, granulocytes, and small subpopulations of T and B cells. The a subunit of p150,95, designated CD11c, is a 150-kDa glycoprotein that is not expressed by T lymphocytes.
The LFA-1 family of glycoproteins is comprised of important adhesion molecules.93,96 The shared b2 subunit has extensive sequence homology to the b3 subunit of the platelet adhesion receptor glycoprotein IIb/IIIa and the b1 subunit of a family of related adhesion proteins, termed very late activation (VLA) antigens. Many of these receptors function in cell-cell interactions and recognize their ligands at sites that contain the amino acid sequence Arg-Gly-Asp. In addition, the a subunit provides some selectivity. LFA-1, because of its a subunit, binds best to cell surface ligands called intercellular adhesion molecules (ICAMs), namely ICAM-1 (CD54), ICAM-2 (CD102), and ICAM-3 (CD50) (see Chap. 13). ICAM-1 and ICAM-2 are expressed on endothelial cells as well as antigen-presenting cells. The binding of LFA-1 on lymphocytes to these molecules allows lymphocytes to migrate through blood vessel walls. ICAM-3 is expressed only on leukocytes, including T cells, and is thought to play an important role in the adhesion of T cells with LFA-1 expressed on antigen-presenting cells (Fig. 84-3).
The LFA glycoproteins are required for proper T-cell function and host immunity. Monoclonal antibodies specific for LFA-1 may inhibit T-cell-directed cytolysis of target cells. Furthermore, a few CD8+ or CD4+ cytolytic T-cell clones express MAC-1. Antibodies to CD11b may inhibit conjugate formation between these T-cell clones and their specific target cells and thus block cytotoxic T-lymphocyte-mediated killing. Finally, patients with an inherited deficiency in the ability to produce the common b2 subunit (CD18) suffer from recurrent life-threatening bacterial and fungal infections and rarely survive beyond childhood.
The LFA molecules are important for initial T-cell interactions with antigen-presenting cells. LFA-1, CD2, and ICAM-3 on the T cell interact with ICAM-1, ICAM-2, LFA-1, and LFA-3 on the antigen-presenting cell (Fig. 84-3). This provides time for the T cell to sample large numbers of MHC molecules on the plasma membrane of the antigen-presenting cell for the presence of specific peptide antigen. When a naive T cell recognizes its specific peptide in the context of the MHC, signaling through the T-cell receptor induces a conformational change in LFA-1 that greatly increases its affinity for ICAM-1 and ICAM-2. This stabilizes the association between the antigen-specific T cell and the antigen-presenting cell. This association can last for several days during which time the naive T cell proliferates, forming daughter cells that also adhere to the antigen-presenting cell and that differentiate into armed effector T cells.
CD2 is a glycoprotein of approximately 50 kDa found on all T lymphocytes, large granular lymphocytes, and thymocytes.97 CD2 facilitates cell-cell adhesion by binding to LFA-3, a 55- to 70-kDa surface glycoprotein that is expressed on erythrocytes and leukocytes as well as on endothelial, epithelial, and connective tissue cells in most organ studies (Fig. 84-3) (see Chap. 13). Monoclonal antibodies that bind CD2 may inhibit a variety of T-lymphocyte functions, including antigen-specific T-lymphocyte-proliferative responses to lectins, alloantigens, and soluble antigens. Anti-CD2 inhibits cytotoxic T-lymphocyte-mediated cell killing by binding to the T cell rather than to the target, which generally does not express CD2. On the other hand, antibodies directed against LFA-3 inhibit cytotoxic T-lymphocyte-mediated cell killing by binding to LFA-3 on the target cell, thus blocking interaction of CD2 with LFA-3. T cells can be activated by certain monoclonal antibodies to CD2, apparently independent of the CD3/T-cell receptor complex.98 Thus aside from being a receptor for LFA-3, CD2 also plays a role in transmembrane signal transduction leading to T-cell activation in response to antigen.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn