The TNF family, of which TNF-α is the prototype, contains more than 17 cytokines with important functions in adaptive and innate immunity. Unlike most of the other immunologically important cytokines, many members of the TNF family are transmembrane proteins, a characteristic that gives them distinct properties and limits their range of action. Some, however, can also be released from the membrane in some circumstances. They are usually found as homotrimers of a membrane-bound subunit, although some heterotrimers consisting of different subunits also occur. TNF-α (sometimes called simply TNF) is initially expressed as a trimeric membrane-bound cytokine but can be released from the membrane. The effects of TNF-α are mediated by either of two TNF receptors. TNF receptor I (TNFR-I) is expressed on a wide range of cells, including endothelial cells and macrophages, whereas TNFR-II is expressed largely by lymphocytes. The receptors for cytokines of the TNF family are structurally unrelated to the receptors described above and also have to cluster to become activated. Since TNF-family cytokines are produced as trimers, the binding of these cytokines induces the clustering of three identical receptor subunits. The signaling pathway activated by these receptors is described in Chapter 7, where we see that signaling uses members of the TRAF family to activate the so-called non-canonical NFκB pathway.
Members of the chemokine receptor family are listed in Appendix IV, along with the chemokines they recognize. These receptors have a 7-transmembrane structure and signal by interacting with G-proteins as described in Section 3-2.
3-16 Cytokine receptors of the hematopoietin family are associated with the JAK family of tyrosine kinases, which activate STAT transcription factors.
The signaling chains of the hematopoietin family of cytokine receptors are noncovalently associated with protein tyrosine kinases of the Janus kinase (JAK) family—so called because they have two tandem kinase-like domains and thus resemble the two-headed mythical Roman god Janus. There are four members of the JAK family: Jak1, Jak2, Jak3, and Tyk2. As mice deficient for individual JAK family members show different phenotypes, each kinase must
Chapter 3: The Induced Responses of Innate Immunity
MOVIE 3.7
Fig. 3.26 Many cytokine receptors signal using a rapid pathway called the JAK–STAT pathway.
First panel: many cytokines act via receptors that are associated with cytoplasmic Janus kinases (JAKs). The receptor consists of at least two chains, each associated with a specific JAK. Second panel: binding of ligand brings the two chains together, allowing the JAKs to phosphorylate and activate each other, and then to phosphorylate (red dots) specific tyrosines in the receptor tails. The STAT (signal transducer and activator of transcription) family of proteins have an N-terminal domain that homodimerizes STATs in the cytosol before activation, and an SH2 domain that binds to the tyrosinephosphorylated receptor tails. Third panel: upon binding, the STAT homodimers are phosphorylated by JAKs. Fourth panel: after phosphorylation, STAT proteins reconfigure into a dimer that is stabilized by SH2 domain binding to phosphotyrosine residues on the other STAT. They then translocate to the nucleus, where they bind to and activate the transcription of a variety of genes important for adaptive immunity.
have a distinct function. For example, Jak3 is used by γc for signaling by several of the cytokines described above. Mutations that inactivate Jak3 cause a form of SCID that is not X-linked.