immune tolerance immune tolerance immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that would otherwise have the capacity to elicit an immune response in a given organism. it is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens (see immune response). 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. historical background the phenomenon of immune tolerance was first described by ray d. owen 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 owen 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 leslie brent, 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 secretion of tgf-β, which sensitizes cells to suppression and promotes treg-like cell differentiation secretion of il-10 cytokine absorption leading to cytokine deprivation-mediated apoptosis 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