Cell Communication And Cytokines
Virtually all immune responses involve cells communicating with each other – for instance T cells with B cells (see Figs 18 and 19) or T cells with macrophages (see Figs 18 and 21) – one cell sending signals to another to divide, differentiate, secrete antibody and so on. Cell–cell signalling can occur in two ways: the cells may come into contact, allowing receptor–receptor interactions (for some simple examples see Fig. 3) or a cell can secrete signalling molecules that travel to another cell, often in close proximity but sometimes at a distance.
Molecules that carry out this signalling function are known as cytokines. At least 30 of these are known, and the list can be extended if one includes every cell-derived molecule that acts on another cell. The term is usually restricted to molecules produced by cells with recognized immune function, such as lymphocytes, macrophages, dendritic cells, NK cells, even if some of them can also be made by, or act on, non-immunological cells. Cytokines are proteins of fairly low molecular weight (generally in the range MW 10 000–80 000) and they are completely distinct from that other major population of soluble immunological molecules, antibody, because they do not show any specificity for antigen. Thus, predominantly the same cytokines would be involved in the immune response to measles, tuberculosis and malaria, unlike the situation with antibody.
For practical purposes, the main cytokines are classified into families (right), named after one of their functions, although sometimes the terminology is none too clear; e.g. one of the most important macrophage activators is called gamma interferon (IFNγ) because it, and the other interferons, were discovered through their effect in interfering with virus growth. In the same way tumour necrosis factor (TNF), despite its promising name, is chiefly involved in inflammation – and indeed can actually promote cancer. Most of the cytokines are now available in pure form, and are finding their way into medicine, although, as is the case with TNF, it can sometimes be more important to block their action.
Cytokine receptors are also classified into corresponding families, based on shared structure. These are shown in the figure (centre) with the intracellular pathways (left) by which cytokine–receptor binding leads to biological function. The following chapter describes some of these functions.
TNF Tumour necrosis factor, originally named for its ability in high doses to destroy some tumours but normally a major mediator of the inflammatory response (see Figs 7 and 24). TNF is made mainly by macrophages and most cell types carry receptors for it. The molecule is a trimer of three 17Mr polypeptides. Binding of TNF to its receptor can trigger either apoptosis or cell activation/survival via the NFκB pathway. TNF is the prototype of a family of about a dozen signalling molecules, some of which are secreted, while others (such as Fas) remain attached to the cell.
Interleukins A generic name often used interchangeably with cytokine. IL-1 Although structurally different from TNF, interleukin 1 (IL-1) (and its homologue IL-18) also has a major role in inflammation. IL-1 is also responsible for fever, by acting on the temperature control centre in the hypothalamus. Its receptor belongs to the immunoglobulin super- family (see Fig. 10) and shares an intracellular domain with the toll receptors of innate immunity (see Fig. 5). IL-1 production is regulated by the multimolecular complex called the inflammasome (see Fig. 5).
IL-2–IL-18 These molecules have a wide range of roles in innate and adaptive immunity (see table below and Fig. 24). Their two or three- chain receptors share cytokine-binding and/or signalling subunits, and are collectively known as type I receptors. Some interleukins (e.g. IL-3) have an important role in haemopoiesis, but confusingly some other molecules with related bone marrow activity are referred to as colony- stimulating factors (CSFs). These also bind to type I receptors, which are therefore sometimes known as haemopoietin receptors.
IFN Interferons IFNα and IFNβ are ubiquitous signals of innate immunity, which activate a broad range of antiviral mechanisms in many types of cell. They are produced by almost all cells, but plasmacytoid dendritic cells produce 1000 times more than any other cell type. In contrast, IFNγ is only weakly antiviral, but is a major regulator of macrophage activation. All three cytokines bind to type II receptors, and activate signals broadly similar to type I. The inhibitory cytokine IL-10 also binds to a type II receptor.
TGF-β Transforming growth factor β (not shown in figure). Named for its ability to induce non-adherent growth in cells in culture, TGF-β also inhibits the activity of T cells and macrophages and stimulates IgA production. Thus, like IL-10, it acts as an immunoregulatory molecule. TGF-β signals via members of the SMAD transcription factor family.
Chemokines A large family of molecules responsible for regulating cell traffic (see Fig. 7). Their receptors traverse the cell membrane seven times, a feature of receptors that act by coupling to GTP-binding (G) proteins. They are classified into two groups, CCR and CXC, depending on the spacing of two N-terminal cysteines, and are important (particularly CCR5) as coreceptors for HIV, the AIDS virus (see Fig. 28).
Apoptosis or programmed cell death is the process by which cells ‘commit suicide’. It is important in organ development, the control of lymphocyte numbers, negative selection in the thymus, killing by NK and cytotoxic T cells. Induction of apoptosis by TNF involves activation of caspase enzymes, with eventual damage to mitochondria and degradation of DNA.
Fas, FasL Fas is a member of the TNF receptor family; Fas L is its ligand. Their binding triggers the process of apoptosis.
JAK, STAT Janus kinases (JAK) are receptor-associated kinases with two active sites (hence their name after the two-headed Roman god Janus). Binding of cytokines to type I or II receptors causes receptor dimerization, activation of the JAKs and subsequent recruitment and phosphorylation of signal transducers and activators of transcription (STATs). Activated STATs dimerize, migrate to the nucleus and switch on gene transcription. Molecular defects in the JAK–STAT pathway are associated with severe immunodeficiencies (see Fig. 33).
Ras Small GTP-binding proteins that regulate cytoskeleton, and hence cell shape and movement.
TIR Toll/interleukin receptor domain, common to toll-like receptors (see Fig. 5) and the IL-1 receptor and acting through the NFκB pathway to induce inflammation.
DD Death domains are signalling structures found within the intracellular section of TNF family of receptors. They are named for their part in activating apoptosis, but they also have a role in activating the NFκB pathway.
NFκB A transcription factor predominantly involved in inflammatory responses and also in counteracting apoptosis. It is normally held in check by an inhibitor, IκB (see Fig. 5).
The table below summarizes the main features of the best-studied cytokines. cytokines.