Immune tolerance, or immunological tolerance, or immunotolerance,
is a state of unresponsiveness of the immune system to substances or
tissue that have the capacity to elicit an immune response in given
organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens. Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes
(peripheral). The mechanisms by which these forms of tolerance are
established are distinct, but the resulting effect is similar.
Immune tolerance is important for normal physiology. Central tolerance is the main way the immune system learns to discriminate self from non-self. Peripheral tolerance is key to preventing over-reactivity of the immune system to various environmental entities (allergens, gut microbes, etc.). Deficits in central or peripheral tolerance also cause autoimmune disease, resulting in syndromes such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, autoimmune polyendocrine syndrome type 1 (APS-1), and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX), and potentially contribute to asthma, allergy, and inflammatory bowel disease. And immune tolerance in pregnancy is what allows a mother animal to gestate a genetically distinct offspring with an alloimmune response muted enough to prevent miscarriage.
Tolerance, however, also has its negative tradeoffs. It allows for some pathogenic microbes to successfully infect a host and avoid elimination. In addition, inducing peripheral tolerance in the local microenvironment is a common survival strategy for a number of tumors that prevents their elimination by the host immune system.
Immune tolerance is important for normal physiology. Central tolerance is the main way the immune system learns to discriminate self from non-self. Peripheral tolerance is key to preventing over-reactivity of the immune system to various environmental entities (allergens, gut microbes, etc.). Deficits in central or peripheral tolerance also cause autoimmune disease, resulting in syndromes such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, autoimmune polyendocrine syndrome type 1 (APS-1), and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX), and potentially contribute to asthma, allergy, and inflammatory bowel disease. And immune tolerance in pregnancy is what allows a mother animal to gestate a genetically distinct offspring with an alloimmune response muted enough to prevent miscarriage.
Tolerance, however, also has its negative tradeoffs. It allows for some pathogenic microbes to successfully infect a host and avoid elimination. In addition, inducing peripheral tolerance in the local microenvironment is a common survival strategy for a number of tumors that prevents their elimination by the host immune system.
Historical background
The
phenomenon of immune tolerance was first described by Ray D. Owens in
1945, who noted that dizygotic twin cattle sharing a common placenta
also shared a stable mixture of each other's red blood cells (though not
necessarily 50/50), and retained that mixture throughout life.
Although Owens did not use the term immune tolerance, his study showed
the body could be tolerant of these foreign tissues. This observation
was experimentally validated by Rupert E. Billingham and Peter Medawar
in 1953, who showed by injecting foreign cells into fetal or neonatal
mice, they could become accepting of future grafts from the same foreign
donor. However, they were not thinking of the immunological
consequences of their work at the time: as Medawar explains:
- "We did not set out with the idea in mind of studying the immunological consequences of the phenomenon described by Owen; on the contrary, we had been goaded by Dr. H.P. Donald into trying to devise a foolproof method of distinguishing monozygotic from dizygotic twins... ."
However, these discoveries, and the host of allograft experiments and
observations of twin chimerism they inspired, were seminal for the
theories of immune tolerance formulated by Sir Frank McFarlane Burnet and Frank Fenner, who were the first to propose the deletion of self-reactive lymphocytes to establish tolerance, now termed clonal deletion.
Burnet and Medawar were ultimately credited for "the discovery of
acquired immune tolerance" and shared the Nobel Prize in Physiology or
Medicine in 1960.
Definitions and usage
In
their Nobel Lecture, Medawar and Burnet define immune tolerance as "a
state of indifference or non-reactivity towards a substance that would
normally be expected to excite an immunological response."
Other more recent definitions have remained more or less the same. The
8th edition of Janeway's Immunobiology defines tolerance as
"immunologically unresponsive…to another's tissues.".
Immune tolerance encompasses the range of physiological
mechanisms by which the body reduces or eliminates an immune response to
particular agents. It is used to describe the phenomenon underlying
discrimination of self from non-self, suppressing allergic responses,
allowing chronic infection instead of rejection and elimination, and
preventing attack of fetuses by the maternal immune system.
Typically, a change in the host, not the antigen, is implied. Though some pathogens can evolve to become less virulent in host-pathogen coevolution,
tolerance does not refer to the change in the pathogen, but can be used
to describe the changes in host physiology. Immune tolerance also does
not usually refer to artificially induced immunosuppression
by corticosteroids, lymphotoxic chemotherapy agents, sublethal
irradiation, etc. Nor does it refer to other types of non-reactivity
such as immunological paralysis. In the latter two cases, the host's physiology is handicapped but not fundamentally changed.
Immune tolerance is formally differentiated into central or peripheral;
however, alternative terms such as "natural" or "acquired" tolerance
have at times been used to refer to establishment of tolerance by
physiological means or by artificial, experimental, or pharmacological
means.
These two methods of categorization are sometimes confused, but are
not equivalent—central or peripheral tolerance may be present naturally
or induced experimentally. This difference is important to keep in
mind.
Central tolerance
Central tolerance
refers to the tolerance established by deleting autoreactive lymphocyte
clones before they develop into fully immunocompetent cells. It occurs
during lymphocyte development in the thymus and bone marrow for T and B lymphocytes,
respectively. In these tissues, maturing lymphocytes are exposed to
self-antigens presented by medullary thymic epithelial cells and thymic
dendritic cells, or bone marrow cells. Self-antigens are present due to
endogenous expression, importation of antigen from peripheral sites via
circulating blood, and in the case of thymic stromal cells, expression
of proteins of other non-thymic tissues by the action of the
transcription factor AIRE.
Those lymphocytes that have receptors that bind strongly to
self-antigens are removed by induction of apoptosis of the autoreactive
cells, or by induction of anergy, a state of non-activity.
Weakly autoreactive B cells may also remain in a state of immunological
ignorance where they simply do not respond to stimulation of their B
cell receptor. Some weakly self-recognizing T cells are alternatively
differentiated into natural regulatory T cells (nTreg cells), which act as sentinels in the periphery to calm down potential instances of T cell autoreactivity (see peripheral tolerance below).
The deletion threshold is much more stringent for T cells than
for B cells since T cells alone can cause direct tissue damage.
Furthermore, it is more advantageous for the organism to let its B cells
recognize a wider variety of antigen so it can produce antibodies
against a greater diversity of pathogens. Since the B cells can only be
fully activated after confirmation by more self-restricted T cells that
recognize the same antigen, autoreactivity is held in check.
This process of negative selection ensures that T and B cells
that could initiate a potent immune response to the host's own tissues
are eliminated while preserving the ability to recognize foreign
antigens. It is the step in lymphocyte education that is key for
preventing autoimmunity (entire process detailed here).
Lymphocyte development and education is most active in fetal
development, but continues throughout life as immature lymphocytes are
generated, slowing as the thymus degenerates and the bone marrow shrinks
in adult life.
Peripheral tolerance
Peripheral tolerance develops after T and B cells mature and enter the peripheral tissues and lymph nodes.
It is established by a number of partly overlapping mechanisms that
mostly involve control at the level of T cells, especially CD4+ helper T
cells, which orchestrate immune responses and give B cells the
confirmatory signals they need in order to produce antibodies.
Inappropriate reactivity toward normal self-antigen that was not
eliminated in the thymus can occur, since the T cells that leave the
thymus are relatively but not completely safe. Some will have receptors (TCRs) that can respond to self-antigens that
- are present in such high concentration outside the thymus that they can bind to "weak" receptors.
- the T cell did not encounter in the thymus (such as, tissue-specific molecules like those in the islets of Langerhans, brain, or spinal cord not expressed by AIRE in thymic tissues).
Those self-reactive T cells that escape intrathymic negative
selection in the thymus can inflict cell injury unless they are deleted
or effectively muzzled in the peripheral tissue chiefly by nTreg cells
(see central tolerance above).
Appropriate reactivity toward certain antigens can also be
quieted by induction of tolerance after repeated exposure, or exposure
in a certain context. In these cases, there is a differentiation of
naïve CD4+ helper T cells into induced Treg cells (iTreg cells) in the peripheral tissue or nearby lymphoid tissue (lymph nodes, mucosal-associated lymphoid tissue, etc.). This differentiation is mediated by IL-2 produced upon T cell activation, and TGF-β from any of a variety of sources, including tolerizing dendritic cells (DCs), other antigen presenting cells, or in certain conditions surrounding tissue.
Treg cells
are not the only cells that mediate peripheral tolerance. Other
regulatory immune cells include T cell subsets similar to but
phenotypically distinct from Treg cells, including TR1 cells that make IL-10 but do not express Foxp3, TGF-β-secreting TH3 cells, as well as other less well-characterized cells that help establish a local tolerogenic environment. B cells also express CD22, a non-specific inhibitor receptor that dampens B cell receptor activation. A subset of B regulatory cells that makes IL-10 and TGF-β also exists. Some DCs can make Indoleamine 2,3-dioxygenase (IDO) that depletes the amino acid tryptophan needed by T cells to proliferate and thus reduce responsiveness. DCs also have the capacity to directly induce anergy in T cells that recognize antigen expressed at high levels and thus presented at steady-state by DCs. In addition, FasL expression by immune privileged tissues can result in activation-induced cell death of T cells.
nTreg vs. iTreg cells
The involvement of T cells, later classified as Treg cells,
in immune tolerance was recognized in 1995 when animal models showed
that CD4+ CD25+ T cells were necessary and sufficient for the prevention
of autoimmunity in mice and rats.
Initial observations showed removal of the thymus of a newborn mouse
resulted in autoimmunity, which could be rescued by transplantation of
CD4+ T cells. A more specific depletion and reconstitution experiment
established the phenotype of these cells as CD4+ and CD25+. Later in
2003, experiments showed that Treg cells were characterized by the
expression of the Foxp3 transcription factor, which is responsible for the suppressive phenotype of these cells.
It was assumed that, since the presence of the Treg cells
originally characterized was dependent on the neonatal thymus, these
cells were thymically derived. By the mid-2000s, however, evidence was
accruing of conversion of naïve CD4+ T cells to Treg cells outside of
the thymus.
These were later defined as induced or iTreg cells to contrast them
with thymus-derived nTreg cells.
Both types of Treg cells quieten autoreactive T cell signaling and
proliferation by cell-contact-dependent and -independent mechanisms
including:
- Contact-dependent:
- Granzyme or perforin secretion upon contact
- Upregulation of cAMP after contact, inducing anergy (reduced proliferation and IL-2 signaling)
- Interaction with B7 on T cells
- Downregulation of CD80/CD86 costimultory molecules on antigen presenting cells upon interaction with CTLA-4 or lymphocyte function-associated antigen 1 (LFA-1)
- Contact-independent
nTreg cells and iTreg cells, however, have a few important
distinguishing characteristics that suggest they have different
physiological roles:
- nTreg cells develop in the thymus; iTreg cells develop outside the thymus in chronically inflamed tissue, lymph nodes, spleen, and gut-associated lymphoid tissue (GALT).
- nTreg cells develop from Foxp3- CD25+ CD4+ cells while iTreg cells develop from Foxp3+ CD25- CD4- cells (both become Foxp3+ CD25+CD4+).
- nTreg cells, when activated, require CD28 costimulation, while iTreg cells require CTLA-4 costimulation.
- nTreg cells are specific, modestly, for self-antigen while iTreg cells recognize allergens, commensal bacteria, tumor antigens, alloantigens, and self-antigens in inflamed tissue.
Tolerance in physiology and medicine
Allograft tolerance
Immune
recognition of non-self-antigens typically complicates transplantation
and engrafting of foreign tissue from an organism of the same species (allografts),
resulting in graft reaction. However, there are two general cases in
which an allograft may be accepted. One is when cells or tissue are
grafted to an immune-privileged site that is sequestered from immune
surveillance (like in the eye or testes) or has strong molecular signals
in place to prevent dangerous inflammation (like in the brain). The
second is when a state of tolerance has been induced, either by previous
exposure to the antigen of the donor in a manner that causes immune
tolerance rather than sensitization in the recipient, or after chronic
rejection. Long-term exposure to a foreign antigen from fetal
development or birth may result in establishment of central tolerance,
as was observed in Medawar's mouse-allograft experiments.
In usual transplant cases, however, such early prior exposure is not
possible. Nonetheless, a few patients can still develop allograft
tolerance upon cessation of all exogenous immunosuppressive therapy, a
condition referred to as operational tolerance.
CD4+ Foxp3+ Treg cells, as well as CD8+ CD28- regulatory T cells that
dampen cytotoxic responses to grafted organs, are thought to play a
role. In addition, genes involved in NK cell and γδT cell function associated with tolerance have been implicated for liver transplant patients. The unique gene signatures of these patients implies their physiology may be predisposed toward immune tolerance.
Fetal development
The
fetus has a different genetic makeup than the mother, as it also
translates its father's genes, and is thus perceived as foreign by the
maternal immune system. Women who have borne multiple children by the
same father typically have antibodies against the father's red blood
cell and major histocompatibility complex (MHC) proteins.
However, the fetus usually is not rejected by the mother, making it
essentially a physiologically tolerated allograft. It is thought that
the placental tissues which interface with maternal tissues not only try
to escape immunological recognition by downregulating identifying MHC
proteins but also actively induce a marked peripheral tolerance.
Placental trophoblast cells express a unique Human Leukocyte Antigen (HLA-G) that inhibits attack by maternal NK cells. These cells also express IDO,
which represses maternal T cell responses by amino acid starvation.
Maternal T cells specific for paternal antigens are also suppressed by
tolerogenic DCs and activated iTregs or cross-reacting nTregs. Some maternal Treg cells also release soluble fibrinogen-like proteins 2 (sFGL2), which suppresses the function of DCs and macrophages involved in inflammation and antigen presentation to reactive T cells.
These mechanisms altogether establish an immune-privileged state in the
placenta that protects the fetus. A break in this peripheral tolerance
results in miscarriage and fetal loss.
The microbiome
The
skin and digestive tract of humans and many other organisms is
colonized with an ecosystem of microorganisms that is referred to as the
microbiome.
Though in mammals a number of defenses exist to keep the microbiota at
a safe distance, including a constant sampling and presentation of
microbial antigens by local DCs, most organisms do not react against
commensal microorganisms and tolerate their presence. Reactions are
mounted, however, to pathogenic microbes and microbes that breach
physiological barriers. Peripheral mucosal immune tolerance, in
particular mediated by iTreg cells and tolerogenic antigen-presenting
cells, is thought to be responsible for this phenomenon. In particular,
specialized gut CD103+ DCs that produce both TGF-β and retinoic acid efficiently promotes the differentiation of iTreg cells in the gut lymphoid tissue. Foxp3- TR1 cells that make IL-10 are also enriched in the intestinal lining. Break in this tolerance is thought to underlie the pathogenesis of inflammatory bowel diseases like Crohn's disease and ulcerative colitis.
Oral tolerance and hypersensitivity
Oral tolerance refers to a specific type of peripheral tolerance induced by antigens given by mouth and exposed to the gut mucosa and its associated lymphoid tissues.
The hypo-responsiveness induced by oral exposure is systemic, and can
reduce hypersensitivity reactions in certain cases. Records from 1829
indicate that American Indians would reduce contact hypersensitivity
from poison ivy by consuming leaves of related Rhus species; however,
contemporary attempts to use oral tolerance to ameliorate autoimmune
diseases like rheumatoid arthritis and other hypersensitivity reactions
have been mixed.
The systemic effects of oral tolerance may be explained by the
extensive recirculation of immune cells primed in one mucosal tissue in
another mucosal tissue, allowing extension of mucosal immunity. The same probably occurs for cells mediating mucosal immune tolerance.
Oral tolerance may depend on the same mechanisms of peripheral
tolerance that limit inflammation to bacterial antigens in the
microbiome, since both involve the gut-associated lymphoid tissue. It
may also have evolved to prevent hypersensitivity reactions to food
proteins. It is of immense immunological importance, since it is a continuous natural immunologic event driven by exogenous antigen.
Allergy and hypersensitivity reactions
in general are traditionally thought of as misguided or excessive
reactions by the immune system, possibly due to broken or underdeveloped
mechanisms of peripheral tolerance. Usually, Treg cells, TR1, and Th3 cells at mucosal surfaces suppress type 2 CD4 helper cells, mast cells, and eosinophils, which mediate allergic response. Deficits in Treg cells or their localization to mucosa have been implicated in asthma and atopic dermatitis.
Attempts have been made to reduce hypersensitivity reactions by oral
tolerance and other means of repeated exposure. Repeated administration
of the allergen in slowly increasing doses, subcutaneously or
sublingually appears to be effective for allergic rhinitis. Repeated administration of antibiotics, which can form haptens to cause allergic reactions, can also reduce antibiotic allergies in children.
The tumor microenvironment
Immune tolerance is an important means by which growing tumors,
which have mutated proteins and altered antigen expression, prevent
elimination by the host immune system. It is well recognized that tumors
are a complex and dynamic population of cells composed of transformed
cells as well as stromal cells, blood vessels, tissue macrophages, and other immune infiltrates. These cells and their interactions all contribute to the changing tumor microenvironment,
which the tumor largely manipulates to be immunotolerant so as to avoid
elimination. There is an accumulation of metabolic enzymes that
suppress T cell proliferation and activation, including IDO and arginase, and high expression of tolerance-inducing ligands like FasL, PD-1, CTLA-4, and B7. Pharmacologic monoclonal antibodies targeted against some of these ligands has been effective in treating cancer. Tumor-derived vesicles known as exosomes have also been implicated promoting differentiation of iTreg cells and myeloid derived suppressor cells (MDSCs), which also induce peripheral tolerance.
In addition to promoting immune tolerance, other aspects of the
microenvironment aid in immune evasion and induction of tumor-promoting
inflammation.
Evolution
Though
the exact evolutionary rationale behind the development of
immunological tolerance is not completely known, it is thought to allow
organisms to adapt to antigenic stimuli that will consistently be
present instead of expending considerable resources fighting it off
repeatedly. Tolerance in general can be thought of as an alternative
defense strategy that focuses on minimizing impact of an invader on host
fitness, instead of on destroying and eliminating the invader.
Such efforts may have a prohibitive cost on host fitness. In plants,
where the concept was originally used, tolerance is defined as a reaction norm of host fitness over a range of parasite burdens, and can be measured from the slope of the line fitting these data.
Immune tolerance may constitute one aspect of this defense strategy,
though other types of tissue tolerance have been described.
Schematic of the reaction norm of tolerance. Organisms of genotype 2 are considered more tolerant to the pathogen than organisms of genotype 1.
The advantages of immune tolerance in particular may be seen in
experiments with mice infected with malaria, in which more tolerant mice
have higher fitness at greater pathogen burdens. In addition,
development of immune tolerance would have allowed organisms to reap the
benefits of having a robust commensal microbiome, such as increased
nutrient absorption and decreased colonization by pathogenic bacteria.
Though it seems that the existence of tolerance is mostly
adaptive, allowing an adjustment of the immune response to a level
appropriate for the given stressor, it comes with important evolutionary
disadvantages. Some infectious microbes take advantage of existing
mechanisms of tolerance to avoid detection and/or elimination by the
host immune system. Induction of regulatory T cells, for instance, has been noted in infections with Helicobacter pylori, Listeria monocytogenes, Brugia malayi, and other worms and parasites.
Another important disadvantage of the existence of tolerance may be
susceptibility to cancer progression. Treg cells inhibit anti-tumor NK cells.
The injection of Treg cells specific for a tumor antigen also can
reverse experimentally-mediated tumor rejection based on that same
antigen.
The prior existence of immune tolerance mechanisms due to selection for
its fitness benefits facilitates its utilization in tumor growth.
Tradeoffs between immune tolerance and resistance
Immune
tolerance contrasts with resistance. Upon exposure to a foreign
antigen, either the antigen is eliminated by the standard immune
response (resistance), or the immune system adapts to the pathogen,
promoting immune tolerance instead.
Resistance typically protects the host at the expense of the
parasite, while tolerance reduces harm to the host without having any
direct negative effects on the parasite. Each strategy has its unique costs and benefits for host fitness:
| Costs | Benefits | |
|---|---|---|
| Elimination (resistance) |
|
|
| Tolerance |
|
|
Evolution works to optimize host fitness, so whether elimination or
tolerance occurs depends on which would benefit the organism most in a
given scenario. If the antigen is from a rare, dangerous invader, the
costs of tolerating its presence are high and it is more beneficial to
the host to eliminate it. Conversely, if experience (of the organism or
its ancestors) has showed that the antigen is innocuous, then it would
be more beneficial to tolerate the presence of the antigen rather than
pay the costs of inflammation.
Despite having mechanisms for both immune resistance and
tolerance, any one organism may be overall more skewed toward a tolerant
or resistant phenotype depending on individual variation in both traits
due to genetic and environmental factors.
In mice infected with malaria, different genetic strains of mice fall
neatly along a spectrum of being more tolerant but less resistant or
more resistant but less tolerant.
Patients with autoimmune diseases also often have a unique gene
signature and certain environmental risk factors that predispose them to
disease. This may have implications for current efforts to identify why certain individuals may be disposed to or protected against autoimmunity, allergy, inflammatory bowel disease, and other such diseases.
