Immunotherapy for Infectious Diseases

Cytokines, Cytokine Antagonists, and Growth Factors 119
cytokine to its soluble receptor prevents the cytokine from effecting target cell function.
An analogous approach toward inhibiting cytokine effect by ligand binding may
be used by some viruses that code for receptor-like molecules, e.g., IFN-� (7) and
TNF-� (8), thereby inhibiting the effects of these cytokines on the host cell.
Receptor Families
Cytokine receptors are membrane glycoproteins with a single transmembrane domain
and an external amino terminus. The functional receptor can consist of two or more
subunits, and these subunits can be shared among different cytokines. This sharing of
the receptor subunits among different cytokines may partially explain some of the functional
redundancy and costimulation of their production and activity. The receptors can
be grouped into four families according to similarities in their DNA or amino acid
sequences: the cytokine receptor superfamily, the TNF superfamily, the immunoglobulin
superfamily, and the IFN-R family.
Most cytokine receptors are members of the cytokine receptor superfamily which is
characterized by a conserved amino acid motif in the extracellular portion and in a
region proximal to the membrane (9, 10). This superfamily can be divided into three
subfamilies according to a shared subunit, i.e., those receptors that share the � chain,
the gp 140 � chain, and the gp 130. The receptors in the � chain subfamily consist of
three subunits (�, �, �): the �, and � subunits are members of the superfamily and are
constitutively expressed on T-cells. Heterodimerization of the �� chains mediates signal
transduction. The receptors for IL-13, IL-4, IL-7, IL-9, and IL-15 are members of
this subfamily. An example of the sharing of the subunits of the cytokine receptor is
the IL-2 receptor: IL-2R� is shared by IL-15, and IL-2R� is a subunit of the receptors
for IL-4, IL-7, and IL-9. The subfamily of receptors that share the gp 140 � chain
includes the receptors for IL-3, IL-5, and GM-CSF. Receptors in this subfamily have
two subunits, with the � chain distinct for each receptor. Both the � and � chains are
members of the cytokine receptor superfamily, and signaling is mediated through ligand
interactions of the cytoplasmic regions on the shared � chain. The subfamily that
shares gp 130 includes receptors for IL-6, IL-11, and IL-12. Formation of homodimers
and heterodimers with gp 130 mediates signal transduction by these receptors.
The TNF family of receptors includes two distinct receptors that bind TNF, TNFR-
I (p75), and TNFR-II (p55). These receptors are homologous and bind both TNF-� and
TNF-� with comparable affinity. Interestingly, other receptors in the TNF superfamily
do not bind cytokines, e.g., FAS (CD95), which signals apoptosis of thymocytes (11)
and CD40 ligand, which signals B-cell survival, proliferation, and switch in the Ig isotype
(12). The immunoglobulin superfamily of receptors includes the two receptors for
IL-1 (13). Although both receptors bind IL-1 well, the type I receptor is the active moiety,
and the type II receptor appears to have minimal activity. However, the type II
receptor may be the precursor for soluble IL-1 receptor, which can bind IL-1 after
being shed from the membrane. A newly described member of the IL-1 receptor family
is the receptor for IL-18, which contains a binding and signaling chain that appears
to share signal transduction pathways similar to those of IL-1R (14). Members of the
IFN-R family include the receptors for IFN-�, IFN-�, and IL-10, which are distant
members of the cytokine receptor superfamily. Investigation into the method of gene
transcription through signal transduction from the IFN receptors has become a model
for signal transduction by several cytokines, i.e., the Jak-Stat paradigm.