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164 Part II Cellular Basis of Hematology

Ligands IL-3 IL-5 GM-CSF IL-12 IL-23 IL-35 IL-27 IL-7 TSLP

Receptor
chains
βc/IL-3Rα βc/IL-5Rα βc/GM-CSFRα IL-12Rβ1/IL-12Rβ2 IL-12Rβ1/IL-23R IL-12Rβ2/? gp130/IL-27Rα Rγ/IL-7Rα IL-7Rα/TSLPR
Ligands IL-2 IL-15 IL-4 IL-7 IL-9 IL-21 IL4 IL13

Receptor
chains
Rγ/IL-2Rβ/IL-2Rα Rγ/IL-2Rβ/IL-15Rα Rγ/IL-4Rα Rγ/IL-7Rα Rγ/IL-9α Rγ/IL-21Rα Rγ/IL-4Rα IL-4Rα/IL-13Rα

Ligands IL-6 IL-11 LIF/OSM OSM CNTF /CLC /NP CT-1 IL-27 OSM IL-31

Receptor
chains
gp130/IL-6Rα gp130/IL-11Rα gp130/LIFR gp130/OSMRβ gp130/LIFR/CNTFRα gp130/LIFR/? gp130/IL-27Rα gp130/OSMRβ GPL/OSMRβ
Fig. 16.1 CLASS OR TYPE I CYTOKINES (OFTEN REFERRED TO AS HEMATOPOIETINS) REGU-
LATE DEVELOPMENT, DIFFERENTIATION, AND ACTIVATION OF HEMATOPOIETIC AND
IMMUNE CELLS. Simple depiction of type 1 cytokine receptor subfamilies. IL-3R, IL-5R, and GM-CSFR
share a common βc chain that place them in one group. IL-12 family members include four cytokines. IL-12
and IL-23 share the IL12Rβ1 unit, while IL-12 and IL-35 share the IL-12Rβ2 unit. IL-27 share the gp130
with the IL-6 family. Multiple cytokines (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21) share the common Rγ chain,
which is mutated in a subset of patients with SCID. IL-4R shares a subunit with IL-13R. Both IL-4 and IL-13
drives Th2 response. IL-7R shares one subunit with the thymic stromal lymphopoietin (TSLP). This sharing
of receptor subunit may explain why deletion of the gene encoding IL-7R affects the lymphoid system more
severely than deleting the IL-7 gene. The IL-6 family includes multiple cytokines that all have the signal
transducer gp130. Deleting gp130 results in embryonic lethality. Some IL-6 family members activate more
than one receptor. Oncostatin M (OSM) can work through a heterodimer receptor consisting of gp130 with
OSMRβ or gp130 with leukemia inhibitory factor-receptor (LIF-R). Ciliary neurotrophic factor (CNTF),
cardiotrophin-like cytokine (CLC), and neuropoietin (NP) engage the receptor composed of gp130, LIFR
and CNTFR. Cardiotrophin-1 (CT-1) uses a receptor composed of gp130, LIF-R and another, yet to be
identified subunit. IL-27 shares gp130 with its specific receptor unit. IL-31 receptor is composed of gp130
like receptor (GPL) and OSMRβ.

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SH2-domain-containing proteins (CIS). We will discuss the proposed hematopoietic stem and progenitor or more mature cell populations.
mechanisms of inhibition of these proteins in some detail later. The crystal structures of cytokines bound to the receptors have been
Expression of receptors is also regulated at the level of gene transcrip- illustrated for multiple cytokine families. For most cytokine-receptor
tion, protein translation, internalization, and degradation. couples, more than one cytokine molecule engages more than one
receptor unit at one time to form a complex. For example, two IL-6
MODELS OF LIGAND-RECEPTOR BINDING molecules aggregate with four receptor chains to form a hexameric
and interlocking assembly mediated by a total of 10 symmetry-
AND ACTIVATION related, thermodynamically coupled interfaces (Fig. 16.6). The
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assembly of this hexameric complex occurs sequentially: IL-6 is first
Cytokines usually bind with high affinity to their cognate receptors, engaged by IL-6Rα and then is presented to gp130 in the proper
although low-affinity binding has been documented. The presence geometry to facilitate a cooperative transition into the high-affinity,
and the density of the receptors determine biologic responses in signaling-competent hexamer. This structure also reveals that gp130