PaRt I Immune Effector Mechanisms RECEPTOR FAMILY LIGANDS Cytokine Receptors (a)Immunoglobulin superfamil As noted already, to exert their biological effects, cytokines receptors must first bind to specific receptors expressed on the mem- IL- brane of responsive target cells. Because these receptors are M-CSF expressed by many types of cells, the cytokines can affect a diverse array of cells. Biochemical characterization of cyto- kine receptors initially progressed at a very slow pace because their levels on the membrane of responsive cells is quite low. As with the cytokines themselves, cloning of the genes encod- ing cytokine receptors has led to rapid advances in the iden tification and characterization of these receptors (b) Class I Cytokine Receptors Fall Within Five Families (hematopoietin) Receptors for the various cytokines are quite diverse struc IL-2 IL- turally, but almost all belong to one of five families of recep- IL-3 IL-4 GM-CSF tor proteins( Figure 12-6) 自自> Conser -5 G-CSF Immunoglobulin superfamily receptors IL-6 IL-7 LIF Class I cytokine nown as the IL-9 CNTF hematopoietin IL-11 I L-12 Prolactin Class ll cytokine receptor family (also known as the interferon receptor family (c)Class Il cytokine receptors Many of the cytokine-binding receptors that function in nd hematopoietic systems belong to the cla eceptor family. The members of this receptor fami have conserved amino acid sequence motifs in the extracellu lar domain consisting of four positionally conserved cysteine residues(CCCC)and a conserved sequence of tryptophan- serine-(any amino acid)-tryptophan-serine(wSXWS, where X is the nonconserved amino acid). The receptors for all the (d)TNF receptors cytokines classified as hematopoietins belong to the class I TNFα cytokine receptor family, which also is called the hematopoi- CD40 etin receptor family. The class ll cytokine receptors possess Nerve growth factor (NGF) the conserved CCCC motifs, but lack the wSXWS motif pre- sent in class I cytokine receptors. Initially only the three interferons, a, B, and y, were thought to be ligands for these receptors. However, recent work has shown that the IL-10 receptor is also a member of this group Another feature common to most of the hematopoietin (class I cytokine) and the class lI cytokine receptor families is (e)Chemokine receptors ANTES PF4 MCAF FIGURE 12. Schematic diagrams showing the structural features NAP-2 that define the five types of receptor proteins to which most cytokines bind. The receptors for most of the interleukins belong to the clas tokine receptor family. C refers to conserved cysteineCytokine Receptors As noted already, to exert their biological effects, cytokines must first bind to specific receptors expressed on the mem￾brane of responsive target cells. Because these receptors are expressed by many types of cells, the cytokines can affect a diverse array of cells. Biochemical characterization of cyto￾kine receptors initially progressed at a very slow pace because their levels on the membrane of responsive cells is quite low. As with the cytokines themselves, cloning of the genes encod￾ing cytokine receptors has led to rapid advances in the iden￾tification and characterization of these receptors. Cytokine Receptors Fall Within Five Families Receptors for the various cytokines are quite diverse struc￾turally, but almost all belong to one of five families of recep￾tor proteins (Figure 12-6): ■ Immunoglobulin superfamily receptors ■ Class I cytokine receptor family (also known as the hematopoietin receptor family) ■ Class II cytokine receptor family (also known as the interferon receptor family) ■ TNF receptor family ■ Chemokine receptor family Many of the cytokine-binding receptors that function in the immune and hematopoietic systems belong to the class I cytokine receptor family. The members of this receptor family have conserved amino acid sequence motifs in the extracellu￾lar domain consisting of four positionally conserved cysteine residues (CCCC) and a conserved sequence of tryptophan￾serine-(any amino acid)-tryptophan-serine (WSXWS, where X is the nonconserved amino acid). The receptors for all the cytokines classified as hematopoietins belong to the class I cytokine receptor family, which also is called the hematopoi￾etin receptor family. The class II cytokine receptors possess the conserved CCCC motifs, but lack the WSXWS motif pre￾sent in class I cytokine receptors. Initially only the three interferons, , , and , were thought to be ligands for these receptors. However, recent work has shown that the IL-10 receptor is also a member of this group. Another feature common to most of the hematopoietin (class I cytokine) and the class II cytokine receptor families is 282 PART III Immune Effector Mechanisms RECEPTOR FAMILY LIGANDS (a) Immunoglobulin superfamily receptors IL-1 M-CSF C-Kit S S S S S S (b) Class I cytokine receptors (hematopoietin) IL-2 IL-3 IL-4 IL-5 IL-6 IL-7 IL-9 IL-11 IL-12 IL-13 IL-15 GM-CSF G-CSF OSM LIF CNTF Growth hormone Prolactin Conserved cysteines WSXWS (c) Class II cytokine receptors (interferon) IFN-α IFN-β IFN-γ IL-10 C C C C (d) TNF receptors C1 C3 C2 C1 C3 C2 C1 C3 C2 C1 C3 C2 TNF-α TNF-β CD40 Nerve growth factor (NGF) FAS (e) Chemokine receptors IL-8 RANTES MIP-1 PF4 MCAF NAP-2 G-protein FIGURE 12-6 Schematic diagrams showing the structural features that define the five types of receptor proteins to which most cytokines bind. The receptors for most of the interleukins belong to the class I cytokine receptor family. C refers to conserved cysteine.