The T-Cell Receptor
It had been evident for many years that T lymphocytes have a
surface receptor for antigen, with roughly similar properties to the
antibody on B lymphocytes, but furious controversy raged as to whether the two
molecules were in fact identical. The T-cell receptor (TCR) was finally
identified unambiguously in 1983–4 by the use of monoclonal antibodies to study
the fine structure of the molecule and use of DNA probing to identify the
corresponding genes.
The TCR has the typical domain
structure of an immunoglobulin-family molecule. Its three-dimensional structure
is rather similar to that of one arm of an antibody molecule (see Fig. 14), and
is made up of two major chains (α, β) each of two domains. A second (γδ)
combination is found on some T cells instead of αβ. However, instead of
interacting directly with intact macromolecules as does antibody, the TCR
recognizes very short stretches of peptide antigen bound to an MHC molecule (as
illustrated in the right-hand part of the figure for a T cell of the helper
variety). The α and β chains associate on the cell membrane with other transmembrane proteins to form the CD3 complex.
This complex, in association with other molecules (e.g. CD4, CD8), is
responsible for transducing an activation signal into the T cell. An unusual
feature of the αβ chains of the TCR, which is shared with the heavy and light
chain of the antibody molecule, is that the genes for different parts of each
polypeptide chain do not lie together on the chromosome, so that unwanted
segments of DNA, and subsequently of RNA, have to be excised to bring them
together. This process is known as gene rearrangement and
occurs only in T and B cells, so that in all other cells the genes remain in
their non-functional ‘germline’ configuration. Once this rearrangement has
occurred in an individual lymphocyte, that cell is committed to a unique
receptor, and therefore a unique antigen-recognizing ability. In this and the
following figure, the portions of genes and proteins that are coloured blue are
those thought to have evolved from the primitive V region, although they
do not all show the same degree of variability.
TCR The T-cell receptor. It is made up of one α (MW
50 000) and one β (MW 45 000) chain, each with an outer variable domain, an
inner constant domain and short intramembrane and cytoplasmic regions. Some T
cells, especially early in fetal life and in some organs such as the gut and
skin, express the alternative γδ receptor and seem to recognize a different set
of antigens including some bacterial gly- colipids. γδ T cells are rare in
humans, but are a major proportion of T cells in other animals including cows,
pigs and sheep. The way in which individual T cells are first positively and
then negatively selected in the thymus to ensure they only
recognize self-MHC plus a foreign peptide is described in Fig. 16.
CD3 A complex of three chains, γ (MW 25 000), δ (MW
20 000) and ε (MW 20 000), essential to all T-cell function. Also associated
with the TCR–CD3 complex are two other signalling molecules, ζ and η. All these
molecules contain sequences known as immunoreceptor tyrosine-based activation
motifs (ITAMs), which allow them to bind to phosphorylating enzymes in the cell
and hence lead to T-cell activa- tion. Interaction of antigen (i.e.
MHC plus peptide) with this whole complex causes many TCR complexes to cluster
together on the surface of the cell, forming an ‘immunological synapse’.
CD4 A single-chain molecule (MW 60 000) found on
human helper T cells. It interacts with MHC class II molecules (as shown in the
figure), and is therefore recruited into the vicinity of the TCR, bringing with
it a T-cell-specific kinase, lck, which binds to its cytoplasmic portion and
which facilitates the process of T-cell activation. CD4 is also the major
receptor which HIV uses to enter the T cell (see Fig. 28).
CD8 A molecule (MW 75 000) found on most cytotoxic
T cells. In humans it is composed of two identical chains, but the equivalent
in the mouse has two different chains (Ly2/3). It is involved in interacting
with MHC class I molecules. Because of their close association with the TCR,
CD4 and CD8 are sometimes known as ‘coreceptors’.
Costimulation Binding of the TCR to the MHC–peptide antigen
is not, by itself, sufficient to activate T cells efficiently. T cells need
simultaneously to receive signals via other cell-surface receptors, which bind
ligands on the antigen-presenting cell. Two examples of such ‘costimulatory’
interactions are those between CD2 on the T cell and LFA-3 (CD58) on the
antigen-presenting cell, and between CD28 on the T cell and CD80 (B7.1) or CD86
(B7.2) on the antigen-presenting cell. This is often called the ‘two-signal’
model of T-cell activation (although in reality there are many more than two
signals involved). It has important implications for the induction of tolerance
(see Fig. 22) because when T cells recognize antigen in the absence of the
right costimulation they can become unresponsive to future encounters with
antigen (such T cells are described as tolerant, or sometimes anergic).
Other costimulatory molecules (e.g. CTLA-4 and PD1 on the T cell which interact
with their respective ligands on the antigen-presenting cells) transmit
negative signals that are important to prevent over- activation of T cells.
Blocking these negative interactions is showing promising results as a way of
improving immune responses to chronic viral infections (see Fig. 27) and cancer
(see Fig. 42).
CD45 This transmembrane protein was originally known
as ‘leucocyte common antigen’ because it is found on all white blood cells.
However, on T cells it distinguishes ‘memory’ T cells (those that have already
encountered antigen) from ‘naive’ T cells (those that have yet already
encountered antigen) from ‘naive’ T cells (those that have yet to
encounter antigens). The extracellular portion of CD45 exists in a number
of variant forms. The shortest form (known as CD45Ro) is found on activated and
memory T cells, but not on most naive T cells (see Fig. 15). In contrast, one
of the longer forms (CD45RA) is found predominantly on naive T cells. The
intracellular portion codes for a tyrosine phosphatase, which plays a key part
in TCR regulation via regulation of the tyrosine kinase lck (see above).
Gene rearrangement The
TCR genes contain up to 100 V genes and numerous J and D genes, so that to make
a single chain, one of each must be linked up to the correct C gene. This is
done by excision of intervening DNA sequences and further excision in the mRNA,
eventually producing a single V–D–J–C RNA to code for the polypeptide chain.
When all the possible combinations of α and β chains are taken into account,
the number of different TCR molecules available to an individual may be as high
as 1015 (see also Fig. 10).
Antigen Shown in
the figure as a short peptide, in this case bound by an MHC molecule and then
recognized by the TCR (for details see Fig. 18). The strength of interaction
between one TCR and one MHC– peptide complex is relatively weak, but the
combined effect of many simultaneous interactions on the T cell, aided by
CD4–MHC or CD8– MHC interactions, results in T-cell activation. Interestingly,
some antigen peptides (antagonist peptides) can have the opposite effect, in
that they somehow turn off T-cell activation and make the T cells unresponsive
to further stimulation. Such peptides might have possible therapeutic uses in
regulating unwanted immune reactions such as allergies or autoimmunity.
T-cell activation ultimately results in the transcription of
several hundred genes that determine T-cell proliferation, differentiation and
effector function. A key early event is the movement of many TCR molecules on
the surface of the T cell into the contact area between the T cell and the
antigen-presenting cell (the immunological synapse). This increased local
concentration leads to tyrosine phosphorylation of ITAMs on
the cytoplasmic tails of several of the CD3 chains. This in turn recruits
further tyrosine kinases (e.g. zap) and ultimately leads to activation of transcription
factors, proteins that bind specific sites on DNA and hence regulate
transcription of particular sets of genes. One key step in T cells is the
activation of the transcription factor NF-AT, and it is this step that is
inhibited by cyclosporine and FK506, important immunosuppressants used
clinically to block transplant rejection (see Fig. 39).
IL-2 One of the main events that follows recognition
of antigen by T cells is that the responding T cells undergo several rounds of
cell division (a phenomenon known as clonal expansion). T-cell proliferation is
driven largely by secretion from the T cells themselves of the cytokine
interleukin 2 (IL-2). IL-2 was one of the first of the family of cytokines to
be identified. As well as its major role in inducing T-cell proliferation, it
has effects on B lymphocytes, macrophages, eosinophils, etc. (see Fig. 24).
T-cell activation also results in secretion of many other cytokines (see Figs
21, 23 and 24).
Superantigens There
is one exception to the very high specificity of T cell–peptide–MHC
interactions: certain molecules, e.g. some viruses and staphylococcal
enterotoxins, have the curious ability to bind to both MHC class II and the TCR
β chain outside the peptide-binding site. The result is that a
whole ‘family’ of T cells respond, rather than a single clone,
with excessive and potentially damaging over-production of cytokines.
