Peripheral tolerance

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In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery (after T and B cells egress from primary lymphoid organs). Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. [1] Peripheral tolerance prevents immune response to harmless food antigens and allergens, too. [2]

Contents

Deletion of self-reactive T cells in the thymus is only 60-70% efficient, and naive T cell repertoire contains a significant portion of low-avidity self-reactive T cells. These cells can trigger an autoimmune response, and there are several mechanisms of peripheral tolerance to prevent their activation. [3] Antigen-specific mechanisms of peripheral tolerance include persistent of T cell in quiescence, ignorance of antigen and direct inactivation of effector T cells by either clonal deletion, conversion to regulatory T cells (Tregs) or induction of anergy. [4] [3] Tregs, which are also generated during thymic T cell development, further suppress the effector functions of conventional lymphocytes in the periphery. [5] Dendritic cells (DCs) participate in the negative selection of autoreactive T cells in the thymus, but they also mediate peripheral immune tolerance through several mechanisms. [6]

Dependence of a particular antigen on either central or peripheral tolerance is determined by its abundance in the organism. [7] B cell peripheral tolerance is much less studied and is largely mediated by B cell dependence on T cell help.

Cells mediating peripheral tolerance

Regulatory T cells

Tregs are the central mediators of immune suppression and they play a key role in maintaining peripheral tolerance. The master regulator of Treg phenotype and function is Foxp3. Natural Tregs (nTregs) are generated in the thymus during the negative selection. TCR of nTregs shows a high affinity for self-peptides, Induced Tregs (iTreg) develop from conventional naive helper T cells after antigen recognition in presence of TGF-β and IL-2. iTregs are enriched in the gut to establish tolerance to commensal microbiota and harmless food antigens. [8] Regardless of their origin, once present Tregs use several different mechanisms to suppress autoimmune reactions. These include depletion of IL-2 from the environment, secretion of anti-inflammatory cytokines IL-10, TGF-β and IL-35 [9] and induction of apoptosis of effector cells. CTLA-4 is a surface molecule present on Tregs which can prevent CD28 mediated costimulation of T cells after TCR antigen recognition. [5]  

Tolerogenic DCs

DCs are a major cell population responsible for the initiation of the adaptive immune response. They present short peptides on MHCII, which are recognized by specific TCR. After encountering an antigen with recognition danger or pathogen-associated molecular patterns, DCs start the secretion of proinflammatory cytokines, express costimulatory molecules CD80 and CD86 and migrate to the lymph nodes to activate naive T cells.  [1] However, immature DCs (iDCs) are able to induce both CD4 and CD8 tolerance. The immunogenic potential of iDCs is weak, because of the low expression of costimulatory molecules and a modest level of MHCII. iDCs perform endocytosis and phagocytosis of foreign antigens and apoptotic cells, which occurs physiologically in peripheral tissues. Antigen-loaded iDCs migrate to the lymph nodes, secrete IL-10, TGF-β and present antigen to the naive T cells without costimulation. If the T cell recognizes the antigen, it is turned into the anergic state, depleted or converted to Treg. [10] iDCs are more potent Treg inducers than lymph node resident DCs. [6] BTLA is a crucial molecule for DCs mediated Treg conversion. [11] Tolerogenic DCs express FasL and TRAIL to directly induce apoptosis of responding T cells. They also produce indoleamine 2,3-dioxygenase (IDO) to prevent T cell proliferation. Retinoic acid is secreted to support iTreg differentiation, too. [12] Nonetheless, upon maturation (for example during the infection) DCs largely lose their tolerogenic capabilities. [10]

LNSCs

Aside from dendritic cells, additional cell populations were identified that are able to induce antigen-specific T cell tolerance. These are mainly the members of lymph node stromal cells (LNSCs). LNSCs are generally divided into several subpopulations based on the expression of gp38 (PDPN) and CD31 surface markers. [13] Among those, only fibroblastic reticular cells and lymphatic endothelial cells (LECs) were shown to play a role in peripheral tolerance. Both of those populations are able to induce CD8 T cell tolerance by the presentation of the endogenous antigens on MHCI molecules. [14] [15] LNSCs lack expression of the autoimmune regulator, and the production of autoantigens depends on transcription factor Deaf1. LECs express PD-L1 to engage PD-1 on CD8 T cells to restrict self-reactivity. [16] LNSCs can drive the CD4 T cell tolerance by the presentation of the peptide-MHCII complexes, which they acquired from the DCs. [17] On the other hand, LECs can serve as a self-antigen reservoir and can transport self-antigens to DCs to direct self-peptide-MHCII presentation to CD4 T cells. In mesenteric lymph nodes(mLN), LNSCs can induce Tregs directly by secretion of TGF-β or indirectly by imprinting mLN-resident DCs. [16]

Intrinsic mechanisms of T cell peripheral tolerance

Although the majority of self-reactive T cell clones are deleted in the thymus by the mechanisms of central tolerance, low affinity self-reactive T cells continuously escape to the immune periphery. [7] Therefore, additional mechanisms exist to prevent self-reactive and unrestained T cells responses.

Quiescence

When naive T cells exit the thymus, they are in a quiescent state. That means they are in the G0 stage of the cell cycle and they have low metabolic, transcriptional and translational activities. Quiescence can prevent naive T cell activation after tonic signaling. After antigen exposure and costimulation, naive T cells start the process called quiescence exit, which results in proliferation and effector differentiation. [18]

Ignorance

Self-reactive T cells can fail to initiate immune response after recognition of self-antigen. The intrinsic mechanism of ignorance is when the affinity of TCR to antigen is too low to elicit T cell activation. There is also an extrinsic mechanism. Antigens, which are present in generally low numbers, can´t stimulate T cells sufficiently. [1] Specialized mechanisms ensuring ignorance by the immune system have developed in so-called immune privileged organs. [4] The abundance of antigen and anatomical location is the most important factors in T cell ignorance. In the inflammatory context, T cells can override ignorance and induce autoimmune disease. [3]

Anergy

Anergy is a state of functional unresponsiveness induced upon self antigen recognition. [19] T-cells can be made non-responsive to antigens presented if the T-cell engages an MHC molecule on an antigen presenting cell (signal 1) without engagement of costimulatory molecules (signal 2). Co-stimulatory molecules are upregulated by cytokines (signal 3) in the context of acute inflammation. Without pro-inflammatory cytokines, co-stimulatory molecules will not be expressed on the surface of the antigen presenting cell, and so anergy will result if there is an MHC-TCR interaction between the T cell and the APC. [4]  TCR stimulation leads to translocation of NFAT into the nucleus. In the absence of costimulation, there is no MAPK signaling in T cells and translocation of transcription factor AP-1 into the nucleus is impaired. This disbalance of transcription factors in T cells results in the expression of several genes involved in forming an anergic state. [20]   Anergic T cells show long-lasting epigenetic programming that silences effector cytokine production. Anergy is reversible and T cells can recover their functional responsiveness in the absence of the antigen. [3]  

Peripheral deletion

After T cell response to co-stimulation-deficient antigen, a minor population of T cells develop anergy and a large proportion of T cells are rapidly lost by apoptosis. This cell death can be mediated by intrinsic pro-apoptotic family member BIM. The balance between proapoptotic BIM and the antiapoptotic mediator BCL-2 determine the eventual fate of the tolerized T cell. [3]  There are also extrinsic mechanisms of deletion mediated by the cytotoxic activity of Fas/FasL or TRAIL/TRAILR interaction. [12]

Immunoprivileged organs

Potentially self-reactive T-cells are not activated at immunoprivileged sites, where antigens are expressed in non-surveillanced areas. This can occur in the testes, for instance. Anatomical barriers can separate the lymphocytes from the antigen, an example is the central nervous system (the blood-brain-barrier). Naive T-cells are not present in high numbers in peripheral tissue but stay mainly in the circulation and lymphoid tissue.

Some antigens are at a too low concentration to cause an immune response – a subthreshold stimulation will lead to apoptosis of a T cell.

These sites include the anterior chamber of the eye, the testes, the placenta and the fetus, and the central nervous system. These areas are protected by several mechanisms: Fas-ligand expression binds Fas on lymphocytes inducing apoptosis, anti-inflammatory cytokines (including TGF-beta and interleukin 10) and blood-tissue-barrier with tight junctions between endothelial cells.

In the placenta IDO breaks down tryptophan, creating a "tryptophan desert" micro environment which inhibits lymphocyte proliferation.

Split tolerance

Since many pathways of immunity are interdependent, they do not all need to be tolerised. For example, tolerised T cells will not activate autoreactive B cells. Without this help from CD4 T cells, the B cells will not be activated. [1]

Related Research Articles

<span class="mw-page-title-main">Dendritic cell</span> Accessory cell of the mammalian immune system

A dendritic cell (DC) is an antigen-presenting cell of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and adaptive immune systems.

<span class="mw-page-title-main">T cell</span> White blood cells of the immune system

T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

In immunology, anergy is a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance. An individual in a state of anergy often indicates that the immune system is unable to mount a normal immune response against a specific antigen, usually a self-antigen. Lymphocytes are said to be anergic when they fail to respond to their specific antigen. Anergy is one of three processes that induce tolerance, modifying the immune system to prevent self-destruction.

The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

<span class="mw-page-title-main">Adaptive immune system</span> Subsystem of the immune system

The adaptive immune system, also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates.

<span class="mw-page-title-main">Antigen-presenting cell</span> Cell that displays antigen bound by MHC proteins on its surface

An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T-cells.

Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive cytotoxic CD8+ T cells into activated cytotoxic CD8+ T cells. This process is necessary for immunity against most tumors and against viruses that infect dendritic cells and sabotage their presentation of virus antigens. Cross presentation is also required for the induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination.

Gut-associated lymphoid tissue (GALT) is a component of the mucosa-associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut.

Co-stimulation is a secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell. In the case of T cells, two stimuli are required to fully activate their immune response. During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.

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. 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.

<span class="mw-page-title-main">Antigen presentation</span> Vital immune process that is essential for T cell immune response triggering

Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment, now bound to the major histocompatibility complex (MHC), is transported to the surface of the cell, a process known as presentation, where it can be recognized by a T-cell receptor. If there has been an infection with viruses or bacteria, the cell will present an endogenous or exogenous peptide fragment derived from the antigen by MHC molecules. There are two types of MHC molecules which differ in the behaviour of the antigens: MHC class I molecules (MHC-I) bind peptides from the cell cytosol, while peptides generated in the endocytic vesicles after internalisation are bound to MHC class II (MHC-II). Cellular membranes separate these two cellular environments - intracellular and extracellular. Each T cell can only recognize tens to hundreds of copies of a unique sequence of a single peptide among thousands of other peptides presented on the same cell, because an MHC molecule in one cell can bind to quite a large range of peptides. Predicting which antigens will be presented to the immune system by a certain MHC/HLA type is difficult, but the technology involved is improving.

Certain sites of the mammalian body have immune privilege, meaning they are able to tolerate the introduction of antigens without eliciting an inflammatory immune response. Tissue grafts are normally recognised as foreign antigens by the body and attacked by the immune system. However, in immune privileged sites, tissue grafts can survive for extended periods of time without rejection occurring. Immunologically privileged sites include:

T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3− regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25−FOXP3−LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.

Short Course Immune Induction Therapy or SCIIT, is a therapeutic strategy employing rapid, specific, short term-modulation of the immune system using a therapeutic agent to induce T-cell non-responsiveness, also known as operational tolerance. As an alternative strategy to immunosuppression and antigen-specific tolerance inducing therapies, the primary goal of SCIIT is to re-establish or induce peripheral immune tolerance in the context of autoimmune disease and transplant rejection through the use of biological agents. In recent years, SCIIT has received increasing attention in clinical and research settings as an alternative to immunosuppressive drugs currently used in the clinic, drugs which put the patients at risk of developing infection, cancer, and cardiovascular disease.

Lymph node stromal cells are essential to the structure and function of the lymph node whose functions include: creating an internal tissue scaffold for the support of hematopoietic cells; the release of small molecule chemical messengers that facilitate interactions between hematopoietic cells; the facilitation of the migration of hematopoietic cells; the presentation of antigens to immune cells at the initiation of the adaptive immune system; and the homeostasis of lymphocyte numbers. Stromal cells originate from multipotent mesenchymal stem cells.

Tolerogenic therapy aims to induce immune tolerance where there is pathological or undesirable activation of the normal immune response. This can occur, for example, when an allogeneic transplantation patient develops an immune reaction to donor antigens, or when the body responds inappropriately to self antigens implicated in autoimmune diseases. It must provide absence of specific antibodies for exactly that antigenes.

T-cell receptor revision is a process in the peripheral immune system which is used by mature T cells to alter their original antigenic specificity based on rearranged T cell receptors (TCR). This process can lead either to continuous appearance of potentially self-reactive T cells in the body, not controlled by the central tolerance mechanism in the thymus or better eliminate such self-reactive T cells on the other hand and thus contributing to peripheral tolerance - the extent of each has not been completely understood yet. This process occurs during follicular helper T cell formation in lymph node germinal centers.

Type 1 regulatory cells or Tr1 (TR1) cells are a class of regulatory T cells participating in peripheral immunity as a subsets of CD4+ T cells. Tr1 cells regulate tolerance towards antigens of any origin. Tr1 cells are self or non-self antigen specific and their key role is to induce and maintain peripheral tolerance and suppress tissue inflammation in autoimmunity and graft vs. host disease.

Antigen transfer in the thymus is the transmission of self-antigens between thymic antigen-presenting cells which contributes to the establishment of T cell central tolerance.

Tolerogenic dendritic cells are heterogenous pool of dendritic cells with immuno-suppressive properties, priming immune system into tolerogenic state against various antigens. These tolerogenic effects are mostly mediated through regulation of T cells such as inducing T cell anergy, T cell apoptosis and induction of Tregs. Tol-DCs also affect local micro-environment toward tolerogenic state by producing anti-inflammatory cytokines.

References

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