Immune evasion and immunotolerance

IMMUNOLOGICAL TOLERANCE / IMMUNOTOLERANCE (see also artificial induction of peripheral tolerance as immunotherapy

, T cell tolerance leads to B cell tolerance, too. Naive, effector and and memory T cells can all be tolerized ! Summary of naturally occurring mechanisms :

... against self Ags (autoreactivity)^{ref1,
ref2,
ref3,
ref4} : several HECT and RING E3 proteins have now also been linked to the induction and maintenance of immune self-tolerance: c-Cbl, Cbl-b, GRAIL / RNF128, Itch and Nedd4 each negatively regulate T cell growth factor production and proliferation^ref

central tolerance = negative selection ...

... of B lymphocytes : central deletion of self-reactive B cells is induced by strong B cell receptor (BCR) cross-linking, whereas moderate levels of cross-linking induce anergy^{ref1,
ref2,
ref3,
ref4}. Anergic B cells complete B cell development and enter the peripheral circulation but are short-lived cells, and under normal circumstances, these cells fail to contribute to the Ab repertoire^{ref1,
ref2,
ref3}.
... of T lymphocytes . Only 3% of the T-cell precursors that enter the thymus survive positive and negative selection^ref. This purged population, composed of T cells with receptors of low and intermediate avidity to self, leaves the thymus and inhabits peripheral lymphoid organs . Curiously, the emigrants from the thymus were selected for survival because of their ability to bind to self peptides with low avidity, yet they constitute the population of T cells that deals with foreign antigens. An explanation for this paradox is that a given TcR can cross-react with multiple peptides; this cross-reactivity maintains the flexibility required by the immune system to adapt to a changing environment^ref1,
ref2. Moreover, because foreign antigens are not normally present in the thymus, T cells with the potential for high-avidity binding to foreign peptides evade negative selection and escape into the periphery (i.e., other lymphoid tissues and organs). As :

not all body self-Ag are expressed in thymus
the more stringent negative selection becomes, the greater risk of dangerously narrowing the repertoire available to respond to foreign pathogens

self

peripheral tolerance (first proposed by Richard Gershon^ref) :

^{ref1,
ref2,
ref3}

^{ref1,
ref2,
ref3,
ref4}

control of the magnitude and class of immune responses :

general intrinsic mechanisms : intrinsic mechanisms induced when the TcR engages MHC–antigen-peptide complexes are a major point of control over the magnitude and class of immune responses. One of these mechanisms entails the avidity and duration of binding of the TcR with MHC–antigen-peptide complexes — avid binding of relatively long duration favors activation, whereas a weak, brief encounter does not^ref1,
ref2. Notably, engagement of the receptors can induce not only activation and differentiation of the T cell but also apoptosis^ref. Control of antigen-induced activation of T cells by intrinsic mechanisms : homeostatic control mechanisms are induced during the initial activation of all T cells when the TcR engages complexes of MHC and antigen peptide. T-cell activation depends on the avidity and duration of binding of the receptor to MHC–antigen-peptide complexes^ref1,
ref2, as well as on costimulatory molecules (e.g., CD40L, CD28, and CTLA-4). These initial events influence the outgrowth, function, and death of T cells, as well as their differentiation into subgroups of helper T (T_h) or regulatory T (T_r) cells that secrete distinct arrays of regulatory cytokines. These control mechanisms function in the absence of suppressor cells. Other receptor–ligand interactions are also pivotal. One of them involves CD40L, a cell-surface molecule that makes an early appearance on activated T cells^ref. It is essential for T-cell–induced antibody formation by B cells and for causing antigen-presenting cells (e.g., dendritic cells) to trigger cell-mediated immune responses. The interaction of CD40L with CD40, its receptor on B cells and DCs, causes up-regulation of 2 surface proteins on these cells, CD80 and CD86^ref1,
ref2. When CD80 and CD86 interact with CD28 on T cells, the outcome is T-cell activation; by contrast, an interaction with CTLA-4 on T cells causes anergy (i.e., a nonspecific state of inactivation) or immune tolerance (i.e., an antigen-specific state of inactivation). Blockade of the CD80–CD28 or CD40L–CD40 pathways induces anergy^{ref1,
ref2,
ref3} or tolerance, whereas blockade of CTLA-4 enhances the immune response^ref
regulatory functions exerted by conventional T cells by means of intrinsic mechanisms : the 2 main populations of mature T cells are CD4⁺ (helper) T cells and CD8⁺ (cytotoxic or killer) T cells. Antigen-induced activation of helper cells causes them to differentiate into subgroups of T_h1 and T_h2 cells^{ref1,
ref2,
ref3}. These subgroups produce distinctive cytokines, which constitute another level of control of CD4⁺ T cells^ref. T_h1 cells secrete IFN-g, which induces cellular immune responses and inhibits T_h2 cells. T_h2 cells secrete IL-4 (which participates in activating B cells) and TGF-b and IL-10 (which inhibit T_h1 cells)^{ref1,
ref2,
ref3}. Other cytokine-secreting subgroups of CD4⁺ cells, termed "type 1 regulatory T (T_r1)" or "type 3 regulatory T (T_r3) cells," secrete the immunosuppressive cytokines IL-10, TGF-b, or both^{ref1,
ref2,
ref3}. The emergence of T_h1, T_h2, and other cytokine-secreting T cells after antigen activation has a major role in regulating T-cell functions^{ref1,
ref2,
ref3}. All these cytokine-secreting T cells constitute a set of conventional T cells that exert regulatory functions on immune response to both self and foreign antigens. They are specifically activated by antigen but mediate suppression nonspecifically through their cytokines. Collectively, these cells, by controlling the magnitude and class of immune response, contribute to the nonspecific inhibition of pathogenic autoimmunity.

regulatory T cells involved in self–nonself discrimination : the deletion within the thymus of T cells with high avidity for self antigens not only reduces the risk of pathogenic autoimmunity but also creates a truncated peripheral population of self-reactive T cells with only low or intermediate avidity for self antigens^{ref1,
ref2,
ref3}. In contrast, the peripheral population that can react against foreign antigens contains T cells of low, intermediate, and high avidity. A major function of suppressor T cells is to down-regulate the potentially pathogenic self-reactive T cells without interfering with the response to foreign antigens. The structures recognized by suppressor cells that enable them to regulate the peripheral immune response to achieve the goal of self–nonself discrimination have been the holy grail of the biology of suppressor T cells. The recent discovery that regulatory CD8⁺ T cells selectively down-regulate T cells of intermediate avidity that are activated by either self or foreign antigens represents an example of how suppressor T cells may discriminate self from nonself in the periphery. These CD8⁺ T cells specifically recognize the Qa1–self-peptide complexes, surrogate structures expressed on certain activated T cells as the consequence of intermediate avidity of the interactions between TcRs on T cells and MHC–antigen-peptide complexes presented by APCs^ref1,
ref2. Since the potentially pathogenic self-reactive T cells are included in the pool of T cells that have intermediate avidity, suppression by CD8⁺ T cells averts pathogenic autoimmunity. This mechanism does not affect high-avidity T cells, which are almost exclusively anti-foreign, and thereby optimizes immune responses to foreign antigens^ref1,
ref2. There is emerging evidence that distinct subgroups of CD4⁺, CD8⁺, and NKT cells mediate regulatory mechanisms. Each of these subgroups uses distinctive receptors and effector mechanisms, and each exerts its influence at different stages of the immune response^ref1,
ref2. NKT cells and specialized CD4⁺ regulatory T cells are "natural suppressor cells," which are present in the immune repertoire before the activation of T cells by antigen, and act primarily during the early phases of innate or primary immune responses or both. These 2 subgroups probably effect suppression by regulating the magnitude or class of the immune response. In contrast, CD8⁺ T suppressor cells differentiate into effector cells during the primary immune response and function as suppressor cells during the secondary and memory phases of immunity^{ref1,
ref2,
ref3,
ref4}; they are primarily involved in self–nonself discrimination.

NKT cells : NKT cells are a distinctive population of T cells. They have properties of natural killer cells but express a/b T-cell receptors that consist of an invariant alpha chain (Va24–JaQ) paired preferentially to various Vb chains^ref. These cells specifically recognize glycolipids related to the glycolipid a-galactosylceramide that often occurs in pathogenic microorganisms and tumor cells. The a-galactosylceramide binds to CD1d, an MHC molecule on antigen-presenting cells. The CD1d–glycolipid complex triggers natural killer T cells to lyse targets and secrete cytokines^{ref1,
ref2,
ref3}. Mammalian antigens such as isoglobotrihexosylceramide and bacterial glycosphingolipid antigens are structurally related to a-galactosylceramide and can stimulate NKT cells^{ref1,
ref2,
ref3}. NKT cells were originally thought to mediate the innate immune responses that lyse tumor cells and pathogens^ref, but they also are involved in autoimmune diseases^ref1,
ref2. When stimulated by contact with antigen, NKT cells develop heightened killer-cell activity and secrete large amounts of IL-4, IFN-g, TGF-b, and IL-10, all known to be involved in the activation of cells that mediate inflammation, innate immunity, and T_h2-type immunity^{ref1,
ref2,
ref3,
ref4}. NKT cells influence a variety of autoimmune diseases in animal models. Prominent among these are murine models of insulin-dependent diabetes and multiple sclerosis, which involve primarily T_h1 cells^{ref1,
ref2,
ref3}. In these diseases the secretion by NKT cells of the T_h2-favoring cytokines IL-4 and IL-10 is probably an important inhibitory mechanism^{ref1,
ref2,
ref3}. In the NOD mouse, injection of cell populations enriched for NKT cells prevents type 1 diabetes^{ref1,
ref2,
ref3}, whereas depletion of NKT cells early in the evolution of diabetes accelerates the onset of diabetes^ref. In murine models of IBD and MS, depletion of NKT cells accelerates the onset of disease, while activation of NKT cells by treatment with a-galactosylceramide ameliorates or prevents disease. These effects are abrogated in mice that are deficient in CD1d. NKT cells have also been implicated in human autoimmune diseases. In monozygotic twins that are discordant for type 1 diabetes, the twin with diabetes has fewer V24–JQ NKT cells than the twin without diabetes^ref, suggesting protection against the disease by NKT cells. However, studies that compared patients who had diabetes with healthy controls, including discordant twins, found that the numbers of NKT cells and the production of IL-4 are unaltered during the course of type 1 diabetes. These results do not necessarily refute the hypothesis that NKT cells defend against type 1 diabetes — they may indicate that development of the autoimmune disease is controlled by several subgroups of immunoregulatory cells acting in concert^ref.
specialized CD4⁺ regulatory T cells , initially characterized by the expression of a CD25 molecule on their surface, were identified in studies of the multiple autoimmune diseases that develop in lymphopenic neonatally thymectomized or genetically athymic mice. In these animals, insulinitis, thyroiditis, gastritis, and a wasting disease develop spontaneously. Adoptive transfer of the mice with CD4⁺CD25⁺ T cells inhibits the development of autoimmunity^ref1,
ref2. These experiments indicate that CD4⁺CD25⁺ regulatory cells are directly involved in the suppression of autoimmunity in immunodeficient mice^{ref1,
ref2,
ref3}. In young normal animals, CD4⁺ regulatory T cells emerge from the thymus and populate peripheral lymphoid organs. There they probably persist into adulthood and are responsible, in part, for preventing autoimmunity in immunocompetent adults. However, the idea that these cells are a distinct lineage is complicated by the fact that the CD25 molecule that was originally used to identify them is the a chain of the IL-2R, which is expressed on virtually all T cells during antigen-induced activation. The role of CD4⁺CD25⁺ cells in autoimmunity was pursued in transgenic mice that carried a gene for a pathogenic myelin-specific TcR that is involved in the induction of EAE. Despite the fact that > 95% of the T cells in these mice expressed the pathogenic TcR, EAE did not develop. If, however, the transgenic mice were mated with RAG^–/– mice (which lack the RAG required to form all TcRs except the transgenic receptor), florid experimental autoimmune encephalomyelitis developed in the recombinase-deficient offspring. It seems from this experiment that the very few (< 5%) T lymphocytes with nontransgenic receptors in the transgenic mice could block the induction of EAE^ref. Subsequently, both CD4⁺CD25⁺ and CD4⁺CD25^- cells were found to suppress the initiation of EAE^ref1,
ref2. All this suggests that CD25 is not the essential feature of CD4⁺ regulatory cells. Recently, the transcription factor FOXP3 , a member of the forkhead family of DNA-binding transcription factors^ref1, was found to be highly expressed in CD4⁺ regulatory T cells^ref1,
ref2. Mutations in the FOXP3 gene cause the fatal autoimmune and inflammatory disorder of scurfy in mice and the clinical and molecular features of the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in humans. Both mice with scurfy and patients with the IPEX syndrome have defects in T-cell activation and low numbers and impaired suppressor functions of CD4⁺CD25⁺ T cells^{ref1,
ref2,
ref3}. In mice that overexpress FOXP3, CD4⁺CD25^– and CD4^–CD8⁺ T cells have suppressor activity, indicating that expression of FOXP3 is linked to this function^ref. Moreover, expression of the FOXP3 gene specifies CD4⁺ function of regulatory T cells, irrespective of CD25 expression^ref1,
ref2. Taken together, these data are strong evidence that the presence of FOXP3, and not CD25, defines CD4⁺ regulatory T cells. That activated CD4⁺CD25^– and CD8⁺ T cells express FOXP3 suggests that this transcription factor is, indeed, linked specifically to the suppressor function^{ref1,
ref2,
ref3,
ref4}. In light of these findings, earlier studies of CD4⁺regulatory T cells that relied on CD25 as the defining marker have to be reexamined or reinterpreted. Other cell-surface activation molecules, including CTLA-4 and TNFRSF18 / GITR may also distinguish CD4⁺ regulatory T cells^{ref1,
ref2,
ref3,
ref4}. Analysis of these markers in relation to FOXP3 expression will refine the identification of the CD4⁺ regulatory T cells. A precise definition of these cells is important because clinical interventions employing infusion of CD4⁺ regulatory T cells into patients is now being pursued as immunosuppressive therapy for autoimmune diseases^{ref1,
ref2,
ref3}. Although antigens can specifically activate CD4⁺ regulatory T cells, it is unclear whether the suppressor function of the cells is antigen-specific. The effector phase of CD4⁺ regulatory T cell–mediated suppression does not seem to involve the TcR; antigen presentation by MHC molecules (i.e., MHC restriction), which is necessary for the helper function of CD4⁺ helper cells, is not essential for the suppressor function of CD4⁺ regulatory T cells. The suppression depends, at least in part, on cell contact, but the surface molecules involved in the contact are unknown^ref. TGF-b₁ and IL-10 , which participate in the intrinsic mechanisms of suppression, also have been implicated in suppression by CD4⁺ regulatory T cells. Whether the specialized CD4⁺ regulatory T cells also function by means of self–nonself discrimination is unclear.
CD8⁺ suppressor T cells effect specific immunosuppression by deleting or suppressing potentially pathogenic self-reactive T-cell clones in the periphery. The existence of this pathway was revealed by the following 2 findings: CD8⁺ T cells participate in resistance to the reinduction of EAE^ref1,
ref2, and they suppress relapses of the disease^ref. The mechanism entails preferential down-regulation of potentially pathogenic T-cell clones that have intermediate avidity for peptides derived from MBP. When T cells become activated during their first encounter with conventional self or foreign antigens, an early step is the differential expression of a unique set of self peptides presented by an MHC class Ib molecule — Qa1 in mice and HLA-E in humans — on some but not all activated T cells^{ref1,
ref2,
ref3,
ref4}. The expression of the Qa1–self-peptide complex on antigen-activated T cells is a function of the intermediate-avidity interaction between TcRs on T cells and MHC–antigen-peptide complexes presented by conventional APCs during the T-cell activation^ref. The Qa1–self-peptide complexes, as surrogate structures expressed on target T cells, are recognized by the a/b T-cell receptors on regulatory CD8⁺ T cells and trigger the CD8⁺ T cells to differentiate into effector cells. These effector cells in turn down-regulate any activated intermediate-avidity T cells expressing the same Qa1–self-peptide complexes during the secondary immune response^ref.

⁺

^ref1,
ref2

^ref

⁺

^ref

⁺

^ref

⁺

In vitro

human CD8⁺ T cells can be induced to differentiate into regulatory cells whose function depends on HLA-E, the human homologue of Qa1

^ref1,
ref2

⁺

^{ref1,
ref2,
ref3}

⁺

antibodies specific for HLA-E–self-peptide complexes

T cells that are reactive with tumors often express intermediate-avidity TcRs

⁺

Because the repertoires of anti-self and anti-foreign TcRs that naive T cells display differ owing to negative selection in the thymus, the consequences of selective down-regulation of T cells with intermediate avidity must also differ. On the one hand, autoimmunity is averted because potentially pathogenic self-reactive T cells reside in the pool of intermediate-avidity self-reactive T cells^ref1,
ref2. On the other hand, the selective down-regulation of T cells with intermediate avidity for foreign antigens indirectly augments the outgrowth of T cells with high avidity for foreign antigens (i.e., T cells that are essential for protective immunity)^ref. Thus, a unified mechanism of suppression ensures self-tolerance and optimizes protective immunity^ref

T-cell intrinsic peripheral tolerance mechanisms

T-cell ignorance of self Ags :

self-Ag are sequestered in immunologically privileged or immune-privileged sites. Immune privilege mainly depends on :

lack of lymphatic drainage (e.g. the CNS)
presence of few APCs
presence of physical barriers between the blood and the tissue (called the blood-tissue barriers) made up of epithelial cells :

blood-choroid plexus (a.k.a. blood-CSF) barrier
made up of endothelial cells :

blood-aqueous barrier : the anatomical mechanism that prevents exchange of materials between the chambers of the eye and the blood.
blood-brain barrier (BBB) / blood-cerebral barrier / hematoencephalic barrier (pituitary gland and chemoreceptor trigger zone (CTZ) are located out of the BBB) : the barrier system separating the blood from the parenchyma of the central nervous system. Its anatomical component consists of unique endothelial cells in the brain capillaries, having tight junctions without fenestrations and with few microvilli and few vesicles for fluid transport, the basal membrane of endothelium and glial processes. Its physiologic component in part consists of enzymes unique to the brain endothelia and of active transport via carrier proteins. It depends on src-suppressed C-kinase substrate (SSeCKS) / AKAP12 which decreases the expression of VEGF through AP-1 reduction, stimulates expression of Ang-1 (an antipermeability factor in astrocytes), and increases tight junction proteins in endothelial cells. The view that the central nervous system (CNS) is an immunologically privileged site has been widely accepted based on classic experiments such as those of Medawar (Medawar PB: Immunity of homologous grafted skin. III. The fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye; Br J Exp Pathol 1948, 29:58-69), who showed that rabbit skin allografted into the CNS failed rejection. This immunologic privilege is specifically related to the low levels of MHC class II expression^ref, which is responsible for antigen presentation in the brain. An additional mechanism for maintaining immune privilege is the presence of the blood-brain barrier (BBB), which is a semi-permeable barrier, composed of endothelial cells that restrict the interface between the brain and immune circulatory products. Specific regions of the brain, the circumventricular organs and the pineal gland , lie outside the BBB^ref and are therefore subject to the effects of serum-derived substances including immune factors. Mato's fluorescent granular perithelial (FGP) cells / perivascular microglial cells, which express type I and type II macrophage scavenger receptors, contribute to the BBB function^ref. The CNS has traditionally been regarded as an immunologically privileged organ. This view was based on the existence of the blood-brain barrier, which separates the brain from the immune system; the lack of a conventional lymphatic system including lymph nodes and draining lymphatic vessels; and the inability of the CNS to reject allografts, as well as the absence of MHC antigens on brain cells^ref1,
ref2. Modern neuroimmunology has modified this concept and demonstrated that the immunologically down-regulated phenotype of the brain is partially mediated by an immunosuppressive activity of brain cells^ref1,
ref2 and that the CNS is integrated into a complex, tightly regulated neuroimmune network. It is interesting that, although the normal brain is devoid of a significant number of lymphocytes, highly malignant lymphomas may develop in the brain (see primary central nervous system lymphoma (PCNSL))^ref.

blood-retina barrier

inner blood-retina barrier : endothelium of central retinal artery branches
outer blood-retina barrier : retinal pigment epithelium

(reproduced with permission from Nature Reviews Immunology (Vol 3, No. 11, pp 879-889 (2003)) copyright Macmillan Magazines Ltd)

(reproduced with permission from Nature Reviews Immunology (Vol 3, No. 11, pp 879-889 (2003)) copyright Macmillan Magazines Ltd)

great threat

NK cells : lyse MHC class I^low corneal endothelial cells^ref
T_h1 and T_h2 lymphocytes : trigger immunogenic inflammation, bystander injury to visual axis^ref1,
ref2
macrophages : secrete factors that cause bystander injury
neutrophils : release toxic molecules and promote angiogenesis
complement-fixing antibodies : activate complement
activated complement : promotes indiscriminate inflammation

small threat

cytotoxic T lymphocytes : eliminate MHC class I-expressing target cells with little ancillary inflammation
non-complement-fixing antibodies : neutralize pathogens without attendant inflammation
iC3b : promotes ACAID^ref

TGF-b₂ suppresses the actgivation of T cells, NK cells and macrophages; confers tolerance-promoting properties on APCs^ref1,
ref2
a-MSH converts IFN-g-producing T cells into regulators; inhibits the activation of polymorphonuclear leukocytes^ref1,
ref2
VIP inhibits T-cell activation and differentiation^ref
CGRP inhibits macrophage activation and effector function; impairs APC capacity to promote T_h1 -cell differentiation^ref
TSP causes APCs to activate TGF-b and secrete CXCL2, suppresses APC expression of IL-12 and CD40^ref1,
ref2
MIF inhibits NK-cell killing of target cells^ref
IL-1Ra inhibits pro-inflammatory effects of IL-1a/b^ref
CD46, CD55 and CD59 inhibit complement activation^ref
CD95L suppresses polymorphonuclear leukocyte recruitment and activation^ref

CD95L promotes apoptosis of CD95⁺ T cells and activates polymorphonuclear leukocytes^{ref1,
ref2,
ref3}
CD46, CD55, CD59 and complement receptor related protein (Crry) inhibit complement activation and stability of the membrane attack complex^ref
CD86 (expressed in an immuno-inhibitory manner by the iris pigment epithelium alone) inhibits T-cell activation through CTLA4^ref
galectin-1 (expressed in an immuno-inhibitory manner by the retinal pigment epithelium alone) inhibits T-cell activation through release of soluble factors from retinal pigment epithelium^ref
MHC class Ib (potential effect yet to be shown) inhibits NK cells and certain effector T cells^ref

blood-mammary gland barrier
placental membrane : the semipermeable membrane that separates the fetal from the maternal blood in the intervillous space of placenta. In the human (hemochorial) placenta, it is composed of fetal vascular endothelium, connective tissue, cytotrophoblast, and syncytiotrophoblast, and it becomes thinner as pregnancy progresses. Sometimes inappropriately called the placental barrier; there are only a few substances that cannot pass through the membrane
blood-thymus barrier : a barrier in the thymus which excludes certain substances, possibly constituted by the interposition of a sheet of epithelial cell processes around the periphery of the lobules and between the lymphocytes and the perivascular connective tissue.
blood-testis barrier : a barrier separating the blood from the seminiferous tubules, consisting of special junctional complexes between adjacent Sertoli cells near the base of the seminiferous epithelium

expression of CD178 / FasL on certain tissue cells, hepatocytes and enterocytes during immune responses (induced immune privilege), certain tumor cells (tumour counter-attack) : binding of CD95 / Fas / Apo-1 on inflammatory cells leads to their apoptosis within 3-5 days : apoptotic lymphocytes produce IL-10 and TGF-b₁ (causing immune deviation from T_h1 to T_h2 cytokine secretion profile) and the uptake of apoptotic cells by APCs favours the activation of regulatory cells : by 14 days there is only limited damage, and most of the inflammation is gone. Forced ectopic expression of FasL on many tissues can have both positive and negative effects: in some cases it can enhance allograft survival; in others, it actually induces rejection by calling in a granulocytic response. Up-regulation of both Fas and FasL on both activated B and T lymphocytes cells renders them susceptible to suicide and B-cell fratricide or T-cell fratricide.

^ref

tissues that survive for extended, often indefinite intervals at conventional sites :

eye : cornea , lens , pigment epithelium and retina
brain and spinal cord
placenta
ovary
testis
liver
hamster cheek pouch
certain tumors

sites that allow foreign grafts to survive for extended, often indefinite intervals :

eye : cornea , anterior chamber , vitreous cavity and subretinal space
brain : ventricles and striatum
pregnant uterus
ovary
testis
adrenal cortex
hair follicles
hamster cheek pouch
certain tumors

... the blood to spleen
... cranial nerves into the nasal lymphatics and drain into the cervical lymph nodes
... spinal nerves to other lymph nodes

the amount of non self-Ag doesn't reach the threshold required to trigger a T-cell response

clone deletion by activation-induced cell death (AICD) : as self-Ags cannot be easily cleared, repetitive TcR engagement might occur and trigger AICD, promoted by Pten and IL-2 pathways (in the latter Stat-5A B upregulates CD178 / FasL and down-regulates FLIP), but antagonized by TGF-b₁. Tolerance to tissue-specific antigens might be maintained less stringently than tolerance to more ubiquitous self-antigens. It is rarely complete and serves to decrease the precursor frequency to a level at which it can be replaced by induction of ...
T-cell anergy as a result of down-regulatory interactions : suboptimal stimulation with costimulatory deficient APC fails to downregulate the CKI p27^Kip and elicits cell cycle arrest in early G₁ preventing G₁-to-S transition. CD3/CD28-mediated activation of anergic T cells could overcome G₁ cell cycle block bucell division does not restore Ag responsiveness : only IL-2/IL-2R interaction regulates Ag responsiveness.

for naive T-cells
for activated T-cells

⁺

^ref1,
ref2

OTU domain, ubuiquitin aldehyde binding 1 / otubain-1

otubain-1

otubain-1 ARF1

^ref

phenotype skewing : down-regulation of CXCR5 prevents T cells migration to B-cell areas of secondary lymphoid tissue.

T-cell extrinsic peripheral tolerance mechanisms

interaction with immature APCs (not activated by PRR -PAMP interaction(s)) leads to T-cell anergy or even deletion
produces (they can transfer tolerance to recipient primed hosts : infectious tolerance)
receptor editing replaces autoreactive BCRs by V(D)J recombination, thereby producing novel non-self-reactive Abs^{ref1,
ref2,
ref3}. Thus, editing differs from the other B cell tolerance mechanisms in that this mechanism spares the self-reactive B cell. In mice, receptor editing makes an important contribution to the establishment of the normal Ab repertoire^ref, but little is known about the relative contributions of deletion, anergy, and editing to tolerance in humans. V-preB⁺L⁺ B cells are a recently described subpopulation of normal human B cells found in the circulation and tonsils, and they accumulate in the joints of some patients with rheumatoid arthritis^ref1,
ref2. These cells differ from other peripheral B cells in that in addition to V-preB they also express low levels of recombinase-activating gene (RAG) mRNA. Although the initial analysis was limited to Ig- (L) chain and the V_H5 gene family, which makes a small contribution to the normal repertoire^ref1,
ref2, it showed an unusual Ab repertoire consistent with self-reactivity and Ig- receptor editing^ref. Based on these observations, it was proposed that V-preB⁺L⁺ B cells may represent B cells that have been tolerized^ref1,
ref2. These cells are unusual in that they continue to express genes that are normally turned off during early B cell development and because they express VH5 and Ig- genes with long CDR3s reminiscent of anti-self Abs^{ref1,
ref2,
ref3,
ref4}.

... against non-self Ags :

in immunologically incompetent individuals : immunological incompetence (immune system not acquired the ability to recognise the Ag as non-self yet)

fetuses and newborns : in 1953, Medawar and colleagues established that fetal and neonatal mice could be tolerized to alloantigen, such that the mice could later accept allografts. Both B and T lymphocytes become nonresponsive to specific Ag in the tolerant state. Despite a considerable amount of examination, the mechanism of neonatal tolerance is still unclear. Possibilities include clonal inactivation, suppression, clonal deletion, and immune deviation from T_h1 to T_h2 cytokine secretion profile. It is generally believed that neonatal susceptibility to infection is due to a developmental defect in immune function, particularly a delay in the maturation of effective T_h1 responses. There might be fewer developmental constraints on the CD8⁺ T-cell compartment than on the CD4⁺ T cells.
lymphocytes in colostrum . Breastfed infants are likely to be tolerized to maternal antigens. Infants breastfed by tuberculin-positive mothers become tuberculin-positive, whereas no such sensitization occurs when the infants of tuberculin-positive mothers are not breastfed. Maternal renal allografts have a better survival rate in individuals who were breastfed than in patients who were not.
immunocompromised individuals

adoptive tolerance : immunological tolerance induced by the passive transfer to an irradiated recipient animal of lymphoid cells from a donor rendered tolerant to an antigen

in immunologically competent individuals : peripheral tolerance

pseudotolerance : newly formed antibodies are not detected because they combine with the injected antigen
T-cell clonal anergy / functional deletion : decrease in T_h-to-T_Reg lymphocytes (they can transfer tolerance to recipient primed hosts : infectious tolerance) ratio due to :

route of administration

p.o. administration (oral tolerance) : epithelial cells can present antigens; but, without important costimulatory molecules, the lymphocytes that see this antigen may die or be rendered non-responsive.

orally tolerized T cells have impaired Ca²⁺/NFAT pathway from TcR and impaired p27^kip1 degradation induced by stimulation through IL-2R accompanying cell cycle arrest : they are able to enter B cell follicles only following challenge with Ag in adjuvant, but they remain unable to provide B cell help. Systemic immune responses to soluble oral Ags do not require an organized GALT but are most likely induced by gut-conditioned DCs
orally tolerized B cells have BcRs which remain capable of binding Ag, but are unable to transduce signals because rendered incapable of interacting with CD79a / Iga and CD79b / Igb.
regulated uptake of commensal bacteria from the gut lumen into underlying mucosal tissues enhances rabbit GALT development and repertoire diversification (requiring also bacterial expression of specific stress-response genes induced by gut's harsh environment)^ref : B. fragilis alone results in no GALT development, while introduction of B. fragilis plus Bacillus subtilis does it. In bacteria-free mice, Enterobacter cloacae (and other mouse commensals) are efficiently killed upon uptake by intestinal mucosal macrophage and dendritic cells, but small numbers of live bacteria survive for about 60 hours within dendritic cells : these cells migrate to the mesenteric lymph nodes (not further due to fairly short life span) and induce localized (avoiding induction of unnecessary immune reactions to the loaded dendritic cells in the rest of the body : commensals avoid stimulating increased gut motility and an outpouring of mucus because it would destroy its own home) low-level IgA responses that in turn limit bacterial penetration beyond the intestinal mucosa, yet support lumenal colonization^ref. Aberrant bacterial translocation beyond the intestinal mucosa in neonatally stressed adult rats (separated regularly from their mothers before weaning), accompanied by physiological changes reminiscent of conditions such as irritable bowel syndrome : increased epithelial permeability => increased bacterial translocation => bacteria in mesenteric lymph nodes, liver, and spleen; mucosal mast-cell density was also increased, as was colonic susceptibility to inflammation^ref.
epithelial cells condition mucosal dendritic cells through the constitutive release of TSLP and other mediators, resulting in the induction of 'noninflammatory' dendritic cells. Epithelial cell-conditioned dendritic cells release IL-10 and IL-6 but not IL-12, and they promote the polarization of T cells toward a 'classical' noninflammatory T_h2 response, even after exposure to a T_h1 -inducing pathogen. This control of immune responses seemed to be lost in patients with Crohn disease . Thus, the intimate interplay between intestinal epithelial cells and dendritic cells may help to maintain gut immune homeostasis^ref.
TLR -mediated recognition of commensal bacteria, rather than being an unwanted side-effect, is actually important for maintaining epithelial integrity and for tissue repair : oral administration of dextran sulphate sodium (DSS) as a model of intestinal injury and inflammation, in MyD88, TLR2-, TLR4-deficient mice or mice depleted of all detectable commensal bacteria using antibiotics causes death due to colonic epithelial injury, severe colonic bleeding and anaemia. The increased epithelial injury was not due to uncontrolled growth of commensal bacteria in the absence of restrictive TLR-dependent responses, because commensal depletion using antibiotics did not improve disease. Neither were there any differences in leukocyte infiltration of the colonic epithelium between wild-type and MyD88-deficient mice. Instead, they found that TLR signalling through MyD88 controls homeostasis of the intestinal epithelium.MyD88-deficient mice had increased basal levels of proliferation of colonic-crypt cells, making these cells more susceptible to damage.As a result, intestinal tissue was unable to undergo compensatory proliferation in response to epithelial injury caused by g-irradiation. These mice also have decreased production of cytoprotective and repair factors, such as IL-6 and HSPs, both before and after DSS administration. The administration of purified LPS or lipoteichoic acid completely protected animals^ref

i.v. administration
epicutaneous immunization (ECi)

dose : immunological paralysis results from the injection of ...

repeated administration of very small doses that are below the threshold required for stimulation of an immune response => clonal abortion (low-dose or low-zone tolerance)
repeated administration of very large doses of antigen (e.g. high viral burdens) => clonal exhaustion (TcR-induced apoptosis) with no production of memory cells (high-dose or high-zone tolerance)

Felton's phenomenon : immunologic unresponsiveness or tolerance to pneumococcal polysaccharide induced in mice by administration of large doses of the antigen
Liacopoulos phenomenon : nonspecific immunosuppression to an antigen induced by administration of large doses of an unrelated antigen

^ref

chemical structure : monomeric form
excessive T-independent antigens
split tolerance / immunodeviation / immune deviation : immunologic tolerance that affects either the humoral immune system or the cell-mediated immune system, but not both simultaneously.
competition for, and removal of, peptide–MHC complexes on DCs ('epitope theft') : e.g. the high-affinity interaction of "indifferent" 8.8 T cells with MBP(79–87) strips this epitope from the surface of DCs^ref.

Casitas B-lineage lymphoma b (Cbl-b)

in vivo

⁺

PL-Cg₁

^ref

in vitro

in vivo

^ref

IL-10 -conditioned DCs, decommissioned for recruitment of adaptive immunity, elicit innate inflammatory gene products (including DC inflammatory protein-1 (DCIP1) (which binds to CXCR2 )) in response to danger signals^ref
hepatic versus lymph-node activation of naive CD8⁺ T cells determines whether tolerance or immunity develops to an antigen expressed in the liver. T-cell activation in the lymph nodes results in acute hepatitis, whereas activation in the liver leads to inefficient function and reduces half-life of T cells^ref.
while pathogenic gut bacteria (e.g. Salmonella enteritidis) lead to up-regulation of expression of pro-inflammatory genes by inducing nuclear import of the NFkB subunit RelA, commensal anaerobic gut bacteria (e.g. Bacteroides thetaiotaomicron) attenuate inflammation by exporting from the nucleus into the cytoplasm PPAR-g and the bound RelA in intestinal epithelial-cell cultures (Caco-2 cells)^ref

Web resources : Immune Tolerance Network

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