284 paRI I Immune Effector mechanisms of GM-CSF has been shown to be inhibited by IL-3. Since the signal-transducing B subunit is shared between the re L-3 L-5 GM-CSF ceptors for these two cytokines, their antagonism is due to Low-affinity receptors Exterior competition for a limited number of B subunits by the Membrane cytokine-specific a subunits of the receptors( Figure 12-8c) Interior A similar situation is found among the IL-6 receptor sub- family, which includes the receptors for IL-6, IL-11, leukemia- L阝 subunit inhibitory factor (LIF), oncostatin M(OSM), and ciliary neurotrophic factor(CNTF)(see Figure 12-7b). In this case High-affinit a common signal-transducing subunit called gp130 associ- ates with one or two different cytokine-specific subunits. LIF and osM. which must share certain structural features both bind to the same a subunit. As expected, the cytokines that bind to receptors in this subfamily display overlapping bio- logical activities: IL-6, OSM, and LiF induce synthesis of acute-phase proteins by liver hepatocytes and differentiation of myeloid leukemia cells into macrophages; IL-6, LIE, and CNTF affect neuronal development, and IL-6, IL-ll, and OSM stimulate megakaryocyte maturation and platelet pro duction. The presence of gp130 in all receptors of the IL-6 subfamily explains their common signaling pathways as well as the binding competition for limited gp130 molecules tha is observed among these cytokines A third signal-transducing subunit defines the IL-2 recep tor subfamily, which includes receptors for IL-2, IL-4, IL-7, GM-CSF IL-9, and IL-15(see Figure 12-7c). The IL-2 and the IL-15 receptors are heterotrimers, consisting of a cytokine-specific a chain and two chains-B and y-responsible for signal transduction. The IL-2 receptor y chain functions as the sig nal-transducing subunit in the other receptors in this sub- family, which are all dimers. Recently, it has been shown that congenital X-linked severe combined immunodeficiency (XSCID)results from a defect in the y-chain gene, which maps to the X chromosome. The immunodeficiencies ob served in this disorder are due to the loss of all the cytokine functions mediated by the IL-2 subfamily receptors The IL-2R Is One of the Most Thoroughly Studied Cytokine Receptors Because of the central role of IL-2 and its receptor in the FIGURE 12-8 Interactions between cytokine-specific subunits and a clonal proliferation of T cells, the IL-2 receptor has received common signal-transducing subunit of cytokine receptors.(a)Sche- olete trimeric receptor comprises three distinct subunits- and GM-CSF. The cytokine-specific subunits exhibit low-affinity binding the a, B, and y chains. The p and y chains belong to the class and cannot transduce an activation signal. Noncovalent association of I cytokine receptor family, containing the characteristic CCCC each subunit with a common B subunit yields a high-affinity dimeric re- Figure 12-7c) B subunit, allows the generation of cytokine-specific signals despite the The IL-2 receptor occurs in three forms that exhibit dif- generation of the same signal by the different cytokine receptors shown. ferent affinities for IL-2: the low-affinity monomeric IL-2Ro, ( c)Competition of ligand-binding chains of different receptors for a the intermediate-affinity dimeric IL-2RBy, and the high- common subunit can produce antagonistic effects between cytokines affinity trimeric IL-2RaBy(Figure 12-9). Because the a Here binding of IL-3 by a subunits of the IL-3 receptor allows them to chain is expressed only by activated T cells, it is often referred out-compete a chains of the GM-CSF receptor for B subunits. / Part (a) to as the tAC(T-cell activation)antigen A monoclonal anti- adapted from T Kishimoto et al., 1992, Science 258: 593.of GM-CSF has been shown to be inhibited by IL-3. Since the signal-transducing subunit is shared between the re￾ceptors for these two cytokines, their antagonism is due to competition for a limited number of subunits by the cytokine-specific subunits of the receptors (Figure 12-8c). A similar situation is found among the IL-6 receptor sub￾family, which includes the receptors for IL-6, IL-11, leukemia￾inhibitory factor (LIF), oncostatin M (OSM), and ciliary neurotrophic factor (CNTF) (see Figure 12-7b). In this case, a common signal-transducing subunit called gp130 associ￾ates with one or two different cytokine-specific subunits. LIF and OSM, which must share certain structural features, both bind to the same subunit. As expected, the cytokines that bind to receptors in this subfamily display overlapping bio￾logical activities: IL-6, OSM, and LIF induce synthesis of acute-phase proteins by liver hepatocytes and differentiation of myeloid leukemia cells into macrophages; IL-6, LIF, and CNTF affect neuronal development, and IL-6, IL-11, and OSM stimulate megakaryocyte maturation and platelet pro￾duction. The presence of gp130 in all receptors of the IL-6 subfamily explains their common signaling pathways as well as the binding competition for limited gp130 molecules that is observed among these cytokines. A third signal-transducing subunit defines the IL-2 recep￾tor subfamily, which includes receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 (see Figure 12-7c). The IL-2 and the IL-15 receptors are heterotrimers, consisting of a cytokine-specific chain and two chains— and —responsible for signal transduction. The IL-2 receptor  chain functions as the sig￾nal-transducing subunit in the other receptors in this sub￾family, which are all dimers. Recently, it has been shown that congenital X-linked severe combined immunodeficiency (XSCID) results from a defect in the -chain gene, which maps to the X chromosome. The immunodeficiencies ob￾served in this disorder are due to the loss of all the cytokine functions mediated by the IL-2 subfamily receptors. The IL-2R Is One of the Most Thoroughly Studied Cytokine Receptors Because of the central role of IL-2 and its receptor in the clonal proliferation of T cells, the IL-2 receptor has received intensive study. As noted in the previous section, the com￾plete trimeric receptor comprises three distinct subunits— the , , and  chains. The and  chains belong to the class I cytokine receptor family, containing the characteristic CCCC and WSXWS motifs, whereas the chain has a quite different structure and is not a member of this receptor family (see Figure 12-7c). The IL-2 receptor occurs in three forms that exhibit dif￾ferent affinities for IL-2: the low-affinity monomeric IL-2R, the intermediate-affinity dimeric IL-2R, and the high￾affinity trimeric IL-2R (Figure 12-9). Because the chain is expressed only by activated T cells, it is often referred to as the TAC (T-cell activation) antigen. A monoclonal anti- 284 PART III Immune Effector Mechanisms β α High-affinity receptors β α β α α Low-affinity receptors β subunit α α Exterior Membrane Interior IL-3 IL-5 GM-CSF (a) α Same signal from all three α α (b) IL-3 GM-CSF α α α α α α β β β β β β αα α α α α (c) FIGURE 12-8 Interactions between cytokine-specific subunits and a common signal-transducing subunit of cytokine receptors. (a) Sche￾matic diagram of the low-affinity and high-affinity receptors for IL-3, IL-5, and GM-CSF. The cytokine-specific subunits exhibit low-affinity binding and cannot transduce an activation signal. Noncovalent association of each subunit with a common subunit yields a high-affinity dimeric re￾ceptor that can transduce a signal across the membrane. (b) Associa￾tion of cytokine-specific subunits with a common signaling unit, the subunit, allows the generation of cytokine-specific signals despite the generation of the same signal by the different cytokine receptors shown. (c) Competition of ligand-binding chains of different receptors for a common subunit can produce antagonistic effects between cytokines. Here binding of IL-3 by subunits of the IL-3 receptor allows them to out-compete chains of the GM-CSF receptor for subunits. [Part (a) adapted from T. Kishimoto et al., 1992, Science 258:593.]