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.
