The hematopoietin superfamily of cytokines is quite large and includes non-immune-system growth and differentiation factors such as erythropoietin (which stimulates red blood cell development) and growth hormone, as well as interleukins with roles in innate and adaptive immunity. IL-6 is a member of this superfamily, as is the cytokine GM-CSF, which stimulates the production of new monocytes and granulocytes in the bone marrow. Many of the soluble cytokines made by activated T cells are members of the hematopoietin family. The receptors for the hematopoietin cytokines are tyrosine kinase-associated receptors that form dimers when their cytokine ligand binds. Dimerization initiates intracellular signaling from the tyrosine kinases associated with the cytoplasmic domains of the receptor. Some types of cytokine receptors are composed of two identical subunits, but others have two different subunits. An important feature of cytokine signaling is the large variety of different receptor subunit combinations that occur.
Tumor necrosis factor (TNF) receptors I and II, CD40, Fas (Apo1, CD95), CD30, CD27, nerve growth factor receptor CCR1–10, CXCR1–5, XCR1, CX3CR1 Homodimeric receptors Receptors for erythropoietin and growth hormone Heterodimeric receptors (no common chain) IL-1 family receptors Receptors for IL-13, IFN-˜, IFN-°, IFN-˛, IL-10 Heterodimeric receptors with a common chain Receptors for IL-3, IL-5, GM-CSF share a common chain, CD131 or °c (common °chain) °c Receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 share a common chain, CD132 or ˛c (common ˛chain). IL-2 receptor also has a third chain, a high-affnity subunit IL-2R˜(CD25) ˛c TNF receptor family Chemokine receptor family
These cytokines and their receptors can also be further divided into subfamilies characterized by functional similarities and genetic linkage. For instance, IL-3, IL-4, IL-5, IL-13, and GM-CSF are related structurally, their genes are closely linked in the genome, and they are often produced together by the same kinds of cells. In addition, they bind to closely related receptors, which belong to the family of class I cytokine receptors. The IL-3, IL-5, and GM-CSF receptors form a subgroup that shares a common β chain. Another subgroup of class I cytokine receptors is defined by the use of the common γ chain (γc) of the IL-2 receptor. This chain is shared by receptors for the cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, and is encoded by a gene located on the X chromosome. Mutations that inactivate γc cause an X-linked severe combined immunodeficiency (X-linked SCID) due to inactivation of the signaling pathways for several cytokines—IL-7, IL-15, and IL-2—that are required for normal lymphocyte development (see Section 13-3). More distantly related, the receptor for IFN-γ is a member of a small family of heterodimeric cytokine receptors with some similarities to the hematopoietin receptor family. These so-called class II cytokine receptors (also known as interferon receptors) include the receptors for IFN-α and IFN-β, and the IL-10 receptor. The hematopoietin and interferon receptors all signal through the JAK–STAT pathway described below and activate different combinations of STATs with different effects.