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FIGURE 7-13 The immunologic synapse. A, This figure shows two views of the immunologic synapse in a T cell-APC conjugate (shown as a Nomarski image in panel c). Talin, a protein that associates with the cytoplasmic tail of the LFA-1 integrin, was revealed by an antibody labeled with a green fluorescent dye, and PKC-9, which associates with the TCR complex, was visualized by antibodies conjugated to a red fluorescent dye. In panels a and b, a two-dimensional optical section of the cell contact site along the x-y axis is shown, revealing the central location of PKC-9 and the peripheral location of talin, both in the T cell. In panels d-f, a three-dimensional view of the entire region of cell-cell contact along the x-z axis is provided. Note, again, the central location of PKC-9 and the peripheral accumulation of talin. (Reprinted with permission of MacmiHan Publishers Ltd. from Monks CRF, BA Freiburg, H Kupfer, N Sciaky, and A Kupfer. Three dimensional segregation of supramolecular activation clusters in T cells. Nature 395:82-86, copyright 1998.) B, A schematic view of the synapse, showing talin and LFA-1 in the p-SMAC (green) and PKC-9 and the TCR in the c-SMAC (red).

FIGURE 7-13 The immunologic synapse. A, This figure shows two views of the immunologic synapse in a T cell-APC conjugate (shown as a Nomarski image in panel c). Talin, a protein that associates with the cytoplasmic tail of the LFA-1 integrin, was revealed by an antibody labeled with a green fluorescent dye, and PKC-9, which associates with the TCR complex, was visualized by antibodies conjugated to a red fluorescent dye. In panels a and b, a two-dimensional optical section of the cell contact site along the x-y axis is shown, revealing the central location of PKC-9 and the peripheral location of talin, both in the T cell. In panels d-f, a three-dimensional view of the entire region of cell-cell contact along the x-z axis is provided. Note, again, the central location of PKC-9 and the peripheral accumulation of talin. (Reprinted with permission of MacmiHan Publishers Ltd. from Monks CRF, BA Freiburg, H Kupfer, N Sciaky, and A Kupfer. Three dimensional segregation of supramolecular activation clusters in T cells. Nature 395:82-86, copyright 1998.) B, A schematic view of the synapse, showing talin and LFA-1 in the p-SMAC (green) and PKC-9 and the TCR in the c-SMAC (red).

costimulators (such as CD28), enzymes such as PKC-0, and adaptor proteins that associate with the cytoplasmic tails of the transmembrane receptors. At this portion of the synapse, called the c-SMAC (for central supramolecular activation cluster), the distance between the T cell plasma membrane and that of the APC is about 15 nm. Integrins remain at the periphery of the synapse, where they function to stabilize the binding of the T cell to the APC, forming the peripheral portion of the SMAC called the p-SMAC. In this outer part of the synapse, the two membranes are about 40 nm apart. Many signaling molecules found in synapses are initially localized to regions of the plasma membrane that have a lipid content different from the rest of the cell membrane and are called lipid rafts or glycolipid-enriched microdomains. TCR and costimula-tory receptor signaling is initiated in these rafts, and signaling initiates cytoskeletal rearrangements that allow rafts to coalesce and form the immunologic synapse.

Immunologic synapses may serve a number of functions during and after T cell activation.

• The synapse forms a stable contact between an antigen-specific T cell and an APC displaying that antigen and becomes the site for assembly of the signaling machinery of the T cell, including the TCR complex, corecep-tors, costimulatory receptors, and adaptors. Although TCR signal transduction is clearly initiated before the formation of the synapse and is required for synapse formation, the immunologic synapse itself may provide a unique interface for TCR triggering. T cell activation needs to overcome the problems of a generally low affinity of TCRs for peptide-MHC ligands and the presence of few MHC molecules displaying any one peptide on an APC. The synapse represents a site at which repeated engagement of TCRs may be sustained by this small number of peptide-MHC complexes on the APC, thus facilitating prolonged and effective T cell signaling.

• The synapse may ensure the specific delivery of secretory granule contents and cytokines from a T cell to APCs or targets that are in contact with the T cell. Vectorial delivery of secretory granules containing perforin and granzymes from CTLs to target cells has been shown to occur at the synapse (see Chapter 10). Similarly, CD40L-CD40 interactions are facilitated by the accumulation of these molecules on the T cell and APC interfaces of the immunologic synapse. Some cyto-kines are also secreted in a directed manner into the synaptic cleft, from where they are preferentially delivered to the cell that is displaying antigen to the T lymphocyte.

• The synapse may also be an important site for the turnover of signaling molecules, primarily by monou-biquitination and delivery to late endosomes and lyso-somes. This degradation of signaling proteins may contribute to the termination of T cell activation and is discussed later.

MAP Kinase Signaling Pathways in T Lymphocytes

Small guanine nucleotide-binding proteins (G proteins) activated by antigen recognition stimulate at least three different mitogen-activated protein (MAP) kinases, which in turn activate distinct transcription factors. G proteins are involved in diverse activation responses in different cell types. Two major members of this family activated downstream of the TCR are Ras and Rac. Each activates a different component or set of transcription factors, and together they mediate many cellular responses of T cells.

• The Ras pathway is activated in T cells after TCR ligation, leading to the activation of the extracellular receptor-activated kinase (ERK), a prominent member of the MAP kinase family, and eventually to the activation of downstream transcription factors. Ras is loosely attached to the plasma membrane through covalently attached lipids. In its inactive form, the guanine nucleotide-binding site of Ras is occupied by guano-sine diphosphate (GDP). When the bound GDP is replaced by guanosine triphosphate (GTP), Ras undergoes a conformational change and can then recruit or activate various cellular enzymes, the most important of which is c-Raf. Activation of Ras by GDP/GTP exchange is seen in response to the engagement of many types of receptors in many cell populations, including the TCR complex in T cells. Mutated Ras proteins that are constitutively active (i.e., they constantly assume the GTP-bound conformation) are associated with neoplastic transformation of many cell types. Nonmutated Ras proteins are active GTPases that convert the GTP bound to Ras into GDP, thus returning Ras to its normal, inactive state.

The mechanism of Ras activation in T cells involves the adaptor proteins LAT and Grb-2 (Fig. 7-14). When LAT is phosphorylated by ZAP-70 at the site of TCR clustering, it serves as the docking site for the SH2 domain of Grb-2. Once attached to LAT, Grb-2 recruits the Ras GTP/GDP exchange factor called SOS (so named because it is the mammalian homologue of a Drosophila protein called son of sevenless) to the plasma membrane. SOS catalyzes GTP for GDP exchange on Ras. This generates the GTP-bound form of Ras (written as Ras-GTP), which then activates a "MAP kinase" cascade of three kinases, the first two of which phosphorylate and activate the next kinase in the cascade. The last kinase in the cascade initiated by Ras is a MAP kinase called ERK. Ras-GTP activates a kinase called c-Raf, which then activates a dual-specificity kinase that phosphorylates ERK on closely spaced threonine and tyrosine residues. This dual-specificity kinase is an example of a MAP kinase kinase (a kinase that activates a MAP kinase). The activated ERK MAP kinase translocates to the nucleus and phos-phorylates a protein called Elk, and phosphorylated Elk stimulates transcription of c-Fos, a component of the activation protein 1 (AP-1) transcription factor.

• In parallel with the activation of Ras through recruitment of Grb-2 and SOS, the adaptors phosphorylated by TCR-associated kinases also recruit and activate a GTP/GDP exchange protein called Vav that acts on another small guanine nucleotide-binding protein called Rac (see Fig. 7-14). The Rac-GTP that is generated initiates a parallel MAP kinase cascade, resulting in the activation of a distinct MAP kinase called c-Jun

Recruitment and activation Ras GTP/GDP of adaptor proteins exchange

FIGURE 7-14 The Ras-MAP kinase pathway in T cell activation. ZAP-70 that is activated by antigen recognition phosphorylates membrane-associated adaptor proteins (such as LAT), which then bind another adaptor, Grb-2, that provides a docking site for the GTP/GDP exchange factor SOS. SOS converts Ras^GDP to Ras^GTP. Ras^GTP activates a cascade of enzymes, which culminates in the activation of the MAP kinase ERK. A parallel Rac-dependent pathway generates another active MAP kinase, JNK (not shown).

FIGURE 7-14 The Ras-MAP kinase pathway in T cell activation. ZAP-70 that is activated by antigen recognition phosphorylates membrane-associated adaptor proteins (such as LAT), which then bind another adaptor, Grb-2, that provides a docking site for the GTP/GDP exchange factor SOS. SOS converts Ras^GDP to Ras^GTP. Ras^GTP activates a cascade of enzymes, which culminates in the activation of the MAP kinase ERK. A parallel Rac-dependent pathway generates another active MAP kinase, JNK (not shown).

N-terminal kinase (JNK). JNK is sometimes called stress-activated protein (SAP) kinase because in many cells, it is activated by various forms of noxious stimuli such as ultraviolet light, osmotic stress, or proinflam-matory cytokines such as tumor necrosis factor (TNF) and IL-1. Activated JNK then phosphorylates c-Jun, the second component of the AP-1 transcription factor. A third member of the MAP kinase family, in addition to ERK and JNK, is p38, and it too is activated by Rac-GTP and in turn activates various transcription factors. Rac-GTP also induces cytoskeletal reorganization and may play a role in the clustering of TCR complexes, coreceptors, and other signaling molecules into the synapse.

The activities of ERK and JNK are eventually shut off by the action of dual-specificity protein tyrosine/threonine phosphatases. These phosphatases are induced or activated by ERK and JNK themselves, providing a negative feedback mechanism to terminate T cell activation.

Calcium- and PKC-Mediated Signaling Pathways in T Lymphocytes

TCR signaling leads to the activation of the y1 isoform of the enzyme phospholipase C (PLCyl), and the products of PLCyl-mediated hydrolysis of membrane lipids activate enzymes that induce specific transcription factors in T cells (Fig. 7-15). PLCy1 is a cytosolic enzyme specific for inositol phospholipids that is recruited to the plasma membrane by tyrosine-phosphorylated LAT within minutes of ligand binding to the TCR. Here, the enzyme is phosphorylated by ZAP-70 and by other kinases, such as the Tec family kinase called Itk. Phosphorylated PLCy1 catalyzes the hydrolysis of a plasma membrane phospho-lipid called PIP2, generating two breakdown products, the soluble sugar triphosphate, inositol 1,4,5-trisphosphate (IP3), and membrane-bound diacylglycerol (DAG). IP3 and DAG then activate two distinct downstream signaling pathways in T cells.

IP3 produces a rapid increase in cytosolic free calcium within minutes after Tcell activation. IP3 diffuses through the cytosol to the endoplasmic reticulum, where it binds to its receptor, a ligand-gated calcium channel, and stimulates release of membrane-sequestered calcium stores. The released calcium causes a rapid rise (during a few minutes) in the cytosolic free calcium ion concentration, from a resting level of about 100 nM to a peak of 600 to 1000 nM. The depletion of endoplasmic reticulum calcium is sensed by an endoplasmic reticulum membrane protein called STIM1, which activates a "store-operated" plasma membrane ion channel called a CRAC (calcium release-activated calcium) channel. The result is an influx of extracellular calcium that sustains cytosolic levels at about 300 to 400 nM for more than an hour. A key component of the CRAC channel is a protein called Orai, which was discovered as a gene that is defective in a rare human immunodeficiency disease. Cytosolic free

Extracellular

Recruitment and Hydrolysis Activation activation of PLCy1 of PIP2 of PKC

FIGURE 7-15 T cell signaling downstream of PLCyl. A,

The LAT adaptor protein that is phosphorylated on T cell activation binds the cytosolic enzyme PLCyl, which is phosphorylated by ZAP-70 and other kinases, such as Itk, and activated. Active PLCyl hydrolyzes membrane PIP2 to generate IP3, which stimulates an increase in cytosolic calcium, and DAG, which activates the enzyme PKC. B, Depletion of endoplasmic reticulum calcium is sensed by STIM1. C, STIM1 which induces the opening of the CRAC channel that facilitates entry of extracellular calcium into the cytosol. Orai is a component of the CRAC channel. Increased cyto-solic calcium and PKC then activate various transcription factors, leading to cellular responses.

calcium acts as a signaling molecule by binding to a ubiquitous calcium-dependent regulatory protein called calmodulin. Calcium-calmodulin complexes activate several enzymes, including a protein serine/threonine phosphatase called calcineurin that is important for transcription factor activation, as discussed later.

Diacylglycerol (DAG), the second breakdown product of PIP2, is a membrane-bound lipid that activates the enzyme protein kinase C (PKC). There are several iso-forms of PKC that participate in the generation of active transcription factors, discussed later. The combination of elevated free cytosolic calcium and DAG activates certain isoforms of membrane-associated PKC by inducing a con-formational change that makes the catalytic site of the kinase accessible to its substrates. Numerous downstream proteins are phosphorylated by PKC. The PKC-0 isoform localizes to the immunologic synapse and is involved in the activation and nuclear translocation of the nuclear factor kB (NF-kB) transcription factor. Pathways of NF-kB activation are discussed later in this chapter.

So far, we have described several signal transduction pathways initiated by ligand binding to the TCR that result in the activation of different types of enzymes: small G protein-MAP kinase pathways leading to activation of kinases such as ERK and JNK; a PLCy1-calcium-dependent pathway leading to activation of the phosphatase calcineurin; and a DAG-dependent pathway leading to activation of PKC. Each of these pathways contributes to the expression of genes encoding proteins needed for T cell clonal expansion, differentiation, and effector functions. In the following section, we describe the mechanisms by which these different signaling pathways stimulate the transcription of various genes in T cells.

Activation of Transcription Factors That Regulate T Cell Gene Expression

The enzymes generated by TCR signaling activate transcription factors that bind to regulatory regions of numerous genes in T cells and thereby enhance transcription of thesegenes (Fig. 7-16). Much of our understanding of the transcriptional regulation of genes in T cells is based on analyses of cytokine gene expression. The transcriptional regulation of most cytokine genes in T cells is controlled by the binding of transcription factors to nucleotide sequences in the promoter and enhancer regions of these genes. For instance, the IL-2 promoter, located 5' of the coding exons of this gene, contains a segment of approximately 300 base pairs in which are located binding sites for several different transcription factors. All these sites must be occupied by transcription factors for maximal transcription of the IL-2 gene. Different transcription factors are activated by different cytoplasmic signal trans-duction pathways, and the requirement for multiple transcription factors accounts for the need to activate many signaling pathways after antigen recognition. It is likely that the same principles are true for many genes in T cells, including genes encoding cytokine receptors and effector molecules, although different genes may be responsive to different combinations of transcription factors.

Three transcription factors that are activated in T cells by antigen recognition and appear to be critical for most

T cell responses are nuclear factor of activated T cells

• NFAT is a transcription factor required for the expression of IL-2, IL-4, TNF, and other cytokine genes. NFAT is present in an inactive, serine-phosphorylated form in the cytoplasm of resting T lymphocytes. It is activated by the calcium-calmodulin-dependent phosphatase calcineurin. Calcineurin dephosphory-lates cytoplasmic NFAT, thereby uncovering a nuclear localization signal that permits NFAT to translocate into the nucleus. Once it is in the nucleus, NFAT binds to the regulatory regions of IL-2, IL-4, and other cyto-kine genes, usually in association with other transcription factors, such as AP-1.

The mechanism of activation of NFAT was discovered indirectly by studies of the mechanism of action of the immunosuppressive drug cyclosporine (see Chapter 16). This drug and the functionally similar compound, FK506, are natural products of fungi and are widely used therapeutic agents to treat allograft rejection. They function largely by blocking T cell cytokine gene transcription. Cyclosporine binds to a cytosolic protein called cyclophilin, and FK506 binds to a protein called FK506-binding protein (FKBP). Cyclophilin and FKBP are also called immunophilins. Cyclosporine-cyclophilin complexes and FK506-FKBP complexes bind to and inhibit calcineurin and thereby block translocation of NFAT into the nucleus.

• AP-1 is a transcription factor found in many cell types; it is specifically activated in T lymphocytes by TCR-mediated signals. AP-1 is actually the name for a family of DNA-binding factors composed of dimers of two proteins that bind to one another through a shared structural motif called a leucine zipper. The best characterized AP-1 factor is composed of the proteins Fos and Jun. TCR-induced signals lead to the appearance of active AP-1 in the nucleus of T cells. Activation of AP-1 typically involves synthesis of the Fos protein and phosphorylation of preexisting Jun protein. Transcription and synthesis of Fos can be enhanced by the ERK pathway, as described before, and also by PKC. JNK phosphorylates c-Jun, and AP-1 complexes containing the phosphorylated form of Jun have increased transcription-enhancing activity. AP-1 appears to physically associate with other transcription factors in the nucleus, including NFAT, and works best in combination with NFAT. Thus, AP-1 activation represents a convergence point of several TCR-initiated signaling pathways.

• NF-kB is a transcription factor that is activated in response to TCR signals and is essential for cytokine synthesis. NF-kB proteins are homodimers or het-erodimers of proteins that are homologous to the product of a cellular proto-oncogene called c-rel and are important in the transcription of many genes in diverse cell types, particularly in innate immune cells (see Chapter 4). In resting T cells, NF-kB is present in the cytoplasm in a complex with other proteins called inhibitors of kB (IkBs), which make a nuclear

Phosphorylation, release, and degradation of IkB

Dephosphorylation of cytoplasmic NFAT

MAP kinase, SAP kinase pathways

FIGURE 7-16 Activation of transcription factors in T cells. Multiple signaling pathways converge in antigen-stimulated T cells to generate transcription factors that stimulate expression of various genes (in this case, the IL-2 gene). The calcium-calmodulin pathway activates NFAT, and the Ras and Rac pathways generate the two components of AP-1. Less is known about the link between TCR signals and NF-kB activation. (NF-kB is shown as a complex of two subunits, which in T cells are typically the p50 and p65 proteins, named for their molecular sizes in kilodaltons.) PKC is important in T cell activation, and the PKC-9 isoform is particularly important in activating NF-kB. These transcription factors function coordi-nately to regulate gene expression. Note also that the various signaling pathways are shown as activating unique transcription factors, but there may be considerable overlap, and each pathway may play a role in the activation of multiple transcription factors.

FIGURE 7-16 Activation of transcription factors in T cells. Multiple signaling pathways converge in antigen-stimulated T cells to generate transcription factors that stimulate expression of various genes (in this case, the IL-2 gene). The calcium-calmodulin pathway activates NFAT, and the Ras and Rac pathways generate the two components of AP-1. Less is known about the link between TCR signals and NF-kB activation. (NF-kB is shown as a complex of two subunits, which in T cells are typically the p50 and p65 proteins, named for their molecular sizes in kilodaltons.) PKC is important in T cell activation, and the PKC-9 isoform is particularly important in activating NF-kB. These transcription factors function coordi-nately to regulate gene expression. Note also that the various signaling pathways are shown as activating unique transcription factors, but there may be considerable overlap, and each pathway may play a role in the activation of multiple transcription factors.

localization signal on NF-kB inaccessible, thus preventing the entry of this factor into the nucleus. TCR signals lead to serine phosphorylation of IKBa and then its ubiquitination and proteasomal degradation. The enzymes responsible for phosphorylation of IkB are called IkB kinases, and these are discussed toward the end of this chapter. Once released from IkB, NF-kB is able to migrate into the nucleus and bind to and regulate the promoters of target genes.

The links between different signaling proteins, activation of transcription factors, and functional responses of T cells are often difficult to establish because there are complex and incompletely understood interactions between signaling pathways. Also, for the sake of simplicity, we often discuss signaling in the context of linear pathways, but it is likely that this does not reflect the more complex and interconnected reality. Finally, we have focused on selected pathways to illustrate how antigen recognition may lead to biochemical alterations, but it is clear that many other signaling molecules are also involved in antigen-induced lymphocyte activation.

Modulation of T Cell Signaling by Protein Tyrosine Phosphatases

Tyrosine phosphatases remove phosphate moieties from tyrosine residues on proteins and generally inhibit TCR signaling. Two tyrosine phosphatases that serve an important inhibitory role in lymphocytes and other hematopoietic cells are called SHP-1 and SHP-2 (for SH2 domain-containing phosphatases 1 and 2). Inhibitory phosphatases are typically recruited by inhibitory receptors that are induced after a lymphocyte has been activated by tyrosine kinases. These phosphatases inhibit signal transduction by removing phosphates from tyro-sine residues in key signaling molecules and thus functionally antagonize tyrosine kinases. Another inhibitory phosphatase that does not act on phosphoproteins but rather is specific for an inositol phospholipid is called SHIP (SH2 domain-containing inositol phosphatase). Like SHP-1 and SHP-2, SHIP binds to phosphorylated ITIM sequences on specific inhibitory receptors. SHIP removes a phosphate group from PIP3, a phospholipid in the inner leaflet of the plasma membrane, and thus antagonizes PI3-kinase signaling in lymphocytes.

Although most phosphatases attenuate lymphocyte signaling, one tyrosine phosphatase, CD45, facilitates lymphocyte activation. The CD45 protein is a receptor tyrosine phosphatase expressed in all hematopoietic cells. It is an integral membrane protein whose cytoplasmic tail contains tandem protein tyrosine phosphatase domains. CD45 dephosphorylates inhibitory tyrosine residues in the Src family kinases Lck and Fyn and thus contributes to the generation of active kinases.

Costimulatory Receptors of T Cells

Costimulatory signals are delivered by receptors that recognize ligands that are induced on APCs by microbes and cooperate with TCR signals to augment signaling and activate T cells. The two-signal hypothesis for T cell activation was introduced in Chapter 1. TCR signaling aided by coreceptors drives the T cell's response to foreign structures. In immunologic jargon, this response by the TCR to MHC and peptide on an APC is referred to as signal 1. T cells are fully activated only when a foreign peptide is recognized in the context of the activation of the innate immune system by a pathogen or some other cause of inflammation. Costimulatory ligands represent the danger signals (or signal 2) induced on antigen-presenting cells by microbes. "Foreignness" must combine with "danger" for optimal T cell activation to occur.

The CD28 Family of Costimulatory Receptors

The best defined costimulators for T lymphocytes are a pair of related proteins, called B7-1 (CD80) and B7-2 (CD86), which are expressed on activated dendritic cells, macrophages, and B lymphocytes. The CD28 molecule on T cells is the principal costimulatory receptor for delivery of second signals for T cell activation. The biologic roles of the B7 and CD28 proteins are considered in more detail in Chapter 9.

Another important activating member of the CD28 family is a receptor called ICOS (inducible costimulator), which plays an important role in T follicular helper cell development and will be discussed in Chapters 9 and 11.

The CD2/SLAM Family of Costimulatory Receptors

Although the best studied and most prominent family of costimulatory receptors on T cells is the CD28 family, other proteins also contribute to optimal T cell activation and differentiation. One important family of proteins that plays a role in the activation of T cells and NK cells is a group of proteins structurally related to a receptor called CD2 (Fig. 7-17). CD2 is a glycoprotein present on more than 90% of mature T cells, on 50% to 70% of thymo-cytes, and on NK cells. The molecule contains two extracellular Ig domains, a hydrophobic transmembrane region, and a long (116 amino acid residues) cytoplasmic tail. The principal ligand for CD2 in humans is a molecule called leukocyte function-associated antigen 3 (LFA-3, or CD58), also a member of the CD2 family. LFA-3 is expressed on a wide variety of hematopoietic and non-hematopoietic cells, either as an integral membrane protein or as a phosphatidylinositol-anchored membrane molecule. In mice, the principal ligand for CD2 is CD48, which is also a member of the CD2 family and is distinct from but structurally similar to LFA-3.

CD2 functions both as an intercellular adhesion molecule and as a signal transducer. Some anti-CD2 antibodies increase cytokine secretion by and proliferation of human T cells cultured with anti-TCR/CD3 antibodies, indicating that CD2 signals can enhance TCR-triggered T cell responses. Some anti-CD2 antibodies block conjugate

Dendritic cell

CD48 CD58 SLAM

CD48 CD58 SLAM

2B4 T cell

[] Tyrosine-containing motifs

FIGURE 7-17 Selected costimulatory receptors of the CD2 family and their ligands. 2B4, CD2, and SLAM contain two extracellular Ig-like domains, and their cytoplasmic tails also contain tyrosine-containing motifs. The tyrosine-based motif in the tail regions of SLAM and SLAM family members such as 2B4 is called an ITSM and binds to SAP or SAP-like proteins (not shown).

formation between T cells and other LFA-3-expressing cells, indicating that CD2 binding to LFA-3 also promotes cell-cell adhesion. Such antibodies inhibit both CTL activity and antigen-dependent helper T cell responses. Knockout mice lacking both CD28 and CD2 have more profound defects in T cell responses than do mice lacking either molecule alone. This indicates that CD28 and CD2 may compensate for each other, an example of the redundancy of costimulatory receptors of T cells. On the basis of such findings, anti-CD2 antibodies are currently being tested for their efficacy in psoriasis.

A distinct subgroup of the CD2 family of proteins is known as the SLAM (signaling lymphocytic activation molecule) family. SLAM, like all members of the CD2 family, is an integral membrane protein that contains two extracellular Ig domains and a relatively long cytoplasmic tail. The cytoplasmic tail of SLAM, but not of CD2, contains a specific tyrosine-based motif, TxYxxV/I (where T is a threonine residue, Y is a tyrosine residue, V is a valine, I is an isoleucine, and x is any amino acid), known as an immunoreceptor tyrosine-based switch motif (ITSM) that is distinct from the ITAM and ITIM motifs found in other activating and inhibitory receptors. It is called a switch motif because in some receptors, this motif can orchestrate a "switch" from the binding of a tyrosine phosphatase, SHP-2, in the absence of an adaptor to the binding of other enzymes in the presence of an adaptor called SAP (SLAM-associated protein), thus potentially mediating a change from an inhibitory to an activating function.

The extracellular Ig domains of SLAM are involved in homophilic interactions. SLAM on a T cell can interact with SLAM on a dendritic cell and, as a result, the cytoplasmic tail of SLAM may deliver signals to T cells. The ITSM motif binds to SAP, and the latter forms a bridge between SLAM and Fyn (a Src family kinase that is also physically linked to CD3 proteins in T cells). SLAM and other members of the SLAM family function as costimulatory receptors in T cells, NK cells, and some B cells. As we shall discuss in Chapter 20, mutations in the SH2D1A gene encoding SAP are the cause of a disease called the X-linked lymphoproliferative syndrome (XLP).

An important member of the SLAM family in NK cells, CD8+ T cells, and y8 T cells is called 2B4 (see Fig. 7-17). 2B4 recognizes a known ligand for CD2 called CD48. Like SLAM, the cytoplasmic tail of 2B4 contains ITSM motifs, binds to the SAP adaptor protein, and signals by recruiting Fyn. Defective 2B4 signaling may contribute in a major way to the immune deficit in patients with the X-linked lymphoproliferative syndrome.

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