Tolerance
The evolution of recognition systems that
initiate destruction of ‘non-self’ material obviously brings with it the need
for safeguards to prevent damage to ‘self’. This is a particularly acute
problem for the adaptive immune system, because the production of T-cell and
B-cell receptors involves an element of random gene rearrangement (see Figs 12
and 13), and therefore lymphocytes with receptors directed at ‘self’ will
inevitably emerge in each individual. Furthermore, ‘self’ for one individual is
not always the same as ‘self’ for another. For example, people of blood group A
have red cells that carry antigen A but make antibodies to blood group B, and
vice versa. The AB child of an A father and a B mother inherits the ability to
make both anti-B and anti-A antibodies but must not make either, i.e. it must
be tolerant to A and B. Adaptive immunity, both B and T cell, in fact
protects itself against possible self-reactivity at several stages (as shown in
the figure). It used to be assumed
that elimination of potentially self-reactive clones (negative selection) was the basis of all
unresponsiveness to self, but many other regulatory mechanisms are now
recognized. Nevertheless, self-tolerance is not absolute, and in some cases
failure may lead to self-destructive immune responses (see Fig. 38).
In certain circumstances, normally
antigenic ‘non-self’ materials can trigger these safeguarding mechanisms, a
state known as induced tolerance, which might be very undesirable in
some infections but very useful in the case of an organ transplant. The
mechanisms involved in induced tolerance are likely to be very similar to those
that maintain self-tolerance. Note that tolerance is by definition antigen
specific, and quite distinct from the non-specific unresponsiveness induced
by damage to the immune system as a whole, which is instead described as immunodeficiency (see Fig.
33).
Clonal elimination A cornerstone of Burnet’s clonal selection theory (1959) was the prediction that lymphocytes were
individually restricted in their recognition of antigen and that
self-recognizing ones were eliminated early in life in the primary lymphoid
organs. This is achieved for T cells by negative selection in the thymus (see
Fig. 16), and for B cells in the bone marrow. Negative selection was first
demonstrated convincingly for superantigens, such as those expressed by some
mice endogenous retroviruses, because these delete a substantial proportion of
T cells in the thymus. Neither B-cell nor T-cell deletion during development is
complete, necessitating the existence of mechanisms of tolerance induction
outside the primary lymphoid organs (peripheral tolerance).
Immunological ignorance Some antigens (e.g. those in the chamber of the
eye) do not normally induce self-reactivity, simply because they never come
into contact with cells of the normal immune system. This phenomenon is known
as immunological ignorance. However, if the normal barriers are broken down,
e.g. following injury or during a prolonged infection, these antigens can
escape into the blood, and self-reactivity and damage of the tissue sometimes
results.
Dendritic cells are thought to exist in both immature and
mature states. Immature dendritic cells express MHC molecules but lack a full
complement of costimulatory molecules such as CD80/86 or CD40 (see Fig. 18).
Dendritic cells carry pattern recognition receptors (PRR; see Fig. 5), which
recognize microbial products (such as the cell surface of bacteria) and trigger
maturation. The processing and presentation of antigens, whether they be ‘self’
or ‘non-self’, by immature dendritic cells is thought to deliver a negative
signal to T cells, and hence induce tolerance. In contrast, antigen
presentation by mature dendritic cells results in full T-cell activation. The danger
hypothesis postulates that both self-antigens and foreign antigens,
administered in the absence of inflammation or pathogen-derived maturation
stimuli, trigger tolerance. The hypothesis explains the old observation that soluble
antigen is less immunogenic and more ‘tolerogenic’ than antigen
administered in the presence of adjuvants, because it does not activate
antigen-presenting cells to express the appropriate costimulatory molecules.
Negative signalling in T cells T cells express a number of molecules on their
surface that transmit negative rather than activating signals. Engagement of
these molecules (e.g. CTLA4, PD1) by ligands on the antigen-presenting cell
surface serves to control and limit normal immune responses to prevent
accidental collateral damage to self- tissues. However, this action may also
limit the efficacy of an immune response, e.g. during chronic viral or
bacterial infection or cancer. Antibodies to these molecules have shown promise
for their ability to improve immune responses in these diseases, but the price
may be the risk of some autoimmunity.
B-cell receptors (immunoglobulin) Exposure of B cells to high concentrations
of antigen during their development leads to either clonal elimination (death
of the B cell). B cells against self-antigens present at low concentrations
(less than 10−5 mol/L) survive, but are never normally activated
because they require help from T cells to trigger antibody secretion. This
mechanism also guards against mature B cells that subsequently change their
specificity because of somatic mutation of their V genes (see Figs 13 and 19)
during an immune response. Thus, B-cell tolerance is determined by both
‘central’ tolerance (clonal deletion)
and ‘peripheral’ tolerance (T-cell regulated).
T-cell receptors pass through an important selection process as they appear in the thymus (see Fig. 16), in
which cells with receptors that have a sufficiently high affinity for
self-peptides presented by thymic dendritic cells die by apoptosis and are
therefore clonally deleted. Using transgenic technology, it is possible to
create mice in which all B or T cells carry receptors of a single antigenic
specificity. Despite the limitations of studying such artificial systems, these
mice have been very important in clearly demonstrating clonal elimination and/
or clonal anergy.
Regulatory T cells (TREG, formerly known as suppressor T cells)
TREG cells that inhibit self-reactive lymphocytes are believed to differentiate
during thymic development, and are characterized by the expression of CD4, CD25
(one chain of the IL-2 receptor) and a transcription factor, FoxP3. Elimination
of these subpopulations of cells, either experimentally or genetically, leads
to the development of widespread autoimmunity, emphasizing the importance of
these cells in maintain- ing normal ‘self’ tolerance. Other types of TREG can
be induced, e.g. by administering antigens via the oral route, or by
delivering repeated small doses of antigen. Regulatory or suppressive B cells
have also been demonstrated. The mechanisms whereby regulatory cells inhibit
their target (which is usually a TH) can include the release of the inhibitory
cytokines IL-10 and TGF-β, but other less understood mechanisms probably
contribute. The balance between TH and TREG probably determines the eventual
outcome of most immune responses and there is enormous interest in trying to
expand populations of antigen-specific TREG therapeutically so as to limit
damaging autoimmune diseases (see Fig. 38).
Fetal (or neonatal) administration of antigen was the first method
shown to induce tolerance. It probably operates by a combination of clonal
elimination and deficient antigen presentation, due perhaps to
antigen-presenting cell immaturity, although fetal B cells may also be
particularly tolerizable because of differences in the way their Ig receptors
are replaced (see above). There is some evidence that α-fetoprotein, a major
serum protein in the fetus, can inhibit self-reactive T cells.
Oral route Antigens absorbed through the gut are first
‘seen’ by liver macrophages, which remove immunogenic aggregates, etc., leaving
only soluble ‘tolerogen’. In addition, antigen-presenting cells in the gut may
be specialized for tolerance induction, to prevent immune responses against
food. The gut epithelium contains large numbers of TREG expressing suppressive cytokines such as
IL-10 and TGF-β.
Antibody-induced tolerance Antibodies against some molecules on the
surface of either T cells or antigen-presenting cells can help to induce a
state of tolerance. Tolerance induced in this way is sometimes known as enhancement,
from the ability to enhance the growth of tumours, transplants, etc. Antibodies
to the CD4 molecule are particularly effective at inducing T-cell tolerance to
antigens given at the same time.
High doses of antigen are usually more tolerogenic,
although repeated low doses can also induce tolerance in T cells. As a rule,
T-cell tolerance is easier to induce and lasts longer than B-cell tolerance.
Antigen suicide Antigens coupled to toxic drugs, radioisotopes,
etc. may home in on specific B cells and kill them without exposing other cells
to danger. A similar principle has been tried to eliminate tumour cells using toxins coupled to antibodies (see
Fig. 42).
