Peripheral tolerance is induced when mature T cells recognize self antigens in peripheral tissues, leading to functional inactivation (anergy) or death, or when the self-reactive lymphocytes are suppressed by regulatory T cells (Fig. 1). Each of these mechanisms of peripheral T cell tolerance is described in this section. Peripheral tolerance is clearly important for preventing T cell responses to self antigens that are not present in the thymus, and it also may provide backup mechanisms for preventing autoimmunity in situations where central tolerance to antigens that are expressed in the thymus is incomplete.

Fig1. Peripheral T cell tolerance. A, Normal T cell responses require antigen recognition and costimulation. B, Three major mechanisms of peripheral T cell tolerance are illustrated: cell-intrinsic anergy, suppression by regulatory T cells, and deletion (apoptotic cell death). TCR, T cell receptor.

Antigen recognition without adequate costimulation results in T cell anergy or death or makes T cells sensitive to suppression by regulatory T cells. As noted in previous chapters, naive T lymphocytes need at least two signals to induce their proliferation and differentiation into effector and memory cells: Signal 1 is always antigen, and signal 2 is provided by costimulators that are expressed on APCs, typically as part of the innate immune response to microbes (or to damaged host cells) . It is believed that dendritic cells in normal uninfected tissues and peripheral lymphoid organs are in a resting (or immature) state, in which they express little or no costimulators, such as B7 proteins . These dendritic cells constantly process and display the self antigens that are present in the tissues. T lymphocytes with receptors for the self antigens are able to recognize the antigens and thus receive signals from their antigen receptors (signal 1), but the T cells do not receive strong costimulation because there is no accompanying innate immune response. Thus, the presence or absence of costimulation is a major factor determining whether T cells are activated or tolerized.

Anergy

Anergy in T cells refers to long-lived functional unresponsiveness that is induced when these cells recognize self antigens (Fig. 2). Self antigens are normally displayed with low levels of costimulators, as discussed earlier. Antigen recognition without adequate costimulation is thought to be the basis of anergy induction, by mechanisms that are described later. Anergic cells survive but are incapable of responding to the antigen.

Fig2. T cell anergy. If a T cell recognizes antigen without strong costimulation, the T cell receptors may lose their ability to deliver activating signals, or the T cell may engage inhibitory receptors, such as cytotoxic T lymphocyte–associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), that block activation. APC, Antigen-presenting cells.

The two best-defined mechanisms responsible for the induction of anergy are abnormal signaling by the TCR complex and the delivery of inhibitory signals from receptors other than the TCR complex.

 • When T cells recognize antigens without costimulation, the TCR complex may lose its ability to transmit activating signals. In some cases, this is related to the activation of enzymes (ubiquitin ligases) that modify signaling proteins and target them for intracellular destruction by proteases.

• On recognition of self antigens, T cells also may preferentially use one of the inhibitory receptors of the CD28 family, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4, or CD152) or programmed cell death protein 1 (PD-1, CD279), which were introduced in Chapter 5. Anergic T cells may express higher levels of these inhibitory receptors, which will inhibit responses to subsequent antigen recognition. The functions and mechanisms of action of these receptors are described in more detail below. 

Regulation of T Cell Responses by Inhibitory Receptors

 Immune responses are influenced by a balance between engagement of activating and inhibitory receptors. This idea is established for B and T lymphocytes and natural killer (NK) cells. In T cells, the main activating receptors are the TCR complex and costimulatory receptors such as CD28 (see Chapter 5), and the best-defined inhibitory receptors, also called coinhibitors, are CTLA-4 and PD-1. The functions and mechanisms of action of these inhibitors are complementary (Fig. 3).

Fig3. Mechanisms of action and properties of cytotoxic T lymphocyte–associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). A, CTLA-4 is a competitive inhibitor of the B7-CD28 inter action. B, PD-1 activates a phosphatase that inhibits signals from the TCR complex and CD28. C, Some of the major differences between these checkpoint molecules are summarized. APC, Antigen-presenting cells; TCR, T cell receptor.

• CTLA-4. CTLA-4 is expressed transiently on activated CD4+ T cells and constitutively on regulatory T cells (described later). It functions to suppress the activation of responding T cells. CTLA-4 works by blocking and removing B7 molecules from the surface of APCs, thus reducing costimulation by CD28 and preventing the activation of T cells (see Fig. 3-A). The choice between engagement of CTLA-4 or CD28 is determined by the affinity of these receptors for B7 and the level of B7 expression. CTLA-4 has a higher affinity for B7 molecules than does CD28, so it binds B7 tightly and prevents the binding of CD28. This competition is especially effective when B7 levels are low (as would be expected normally when APCs are displaying self and probably tumor antigens); in these situations, the receptor that is preferentially engaged is the high- affinity blocking receptor CTLA-4. How ever, when B7 levels are high (as in infections), not all the ligands will be occupied by CTLA-4 and some B7 will be available to bind to the low-affinity activating receptor CD28, leading to T cell costimulation.

• PD-1. PD-1 is expressed on CD8+ and CD4+ T cells after antigen stimulation. Its cytoplasmic tail has inhibitory signaling motifs with tyrosine residues that are phosphorylated upon recognition of its ligands PD-L1 or PD-L2. Once phosphorylated, these tyrosines bind a tyrosine phosphatase that inhibits kinase-dependent activating signals from CD28 and the TCR complex (see Fig. 3-B). Because the expression of PD-1 on T cells is increased upon chronic T cell activation and expression of the ligands is increased by cytokines produced during prolonged inflammation, this path way is most active in situations of chronic or repeated antigenic stimulation. This may happen in responses to chronic infections, tumors, and self antigens, when PD-1–expressing T cells encounter the ligand on infected cells, tumor cells, or APCs.

One of the most impressive therapeutic applications of our understanding of these inhibitory receptors is treatment of cancer patients with antibodies that block these receptors. Such treatment leads to enhanced antitumor immune responses and tumor regression in a significant fraction of the patients . This type of therapy has been termed checkpoint blockade, because the inhibitory receptors impose checkpoints in immune responses, and the treatment blocks these checkpoints (“removes the brakes” on immune responses). Predict ably, patients treated with checkpoint blockade often develop autoimmune reactions, consistent with the idea that the inhibitory receptors are constantly functioning to keep autoreactive T cells in check. Rare patients with mutations in one of their two copies of the CTLA4 gene, which reduce expression of the receptor, also develop multiorgan inflammation (and a profound, as yet unexplained, defect in antibody production).

Several other receptors on T cells other than CTLA-4 and PD-1 have been shown to inhibit immune responses and are currently being tested as targets of checkpoint blockade therapy. Some of these receptors are members of the tumor necrosis factor (TNF) receptor family or other protein families. Their role in maintaining tolerance to self antigens is not clearly established. 

Immune Suppression by Regulatory T Cells

Regulatory T cells develop in the thymus or peripheral tissues on recognition of self antigens and suppress the activation of potentially harmful lymphocytes specific for these self antigens (Fig. 4). The majority of self-reactive regulatory T cells probably develop in the thymus , but they may also arise in peripheral lymphoid organs. Most regulatory T cells are CD4+ and express high levels of CD25, the α chain of the interleukin-2 (IL-2) receptor. They also express a transcription factor called FoxP3, which is required for the development and function of the cells. Mutations of the gene encoding FoxP3 in humans or in mice cause a systemic, multiorgan autoimmune disease, demonstrating the importance of FoxP3+ regulatory T cells for the maintenance of self-tolerance. The human disease is known by the acronym IPEX, for immune dysregulation, poly endocrinopathy, enteropathy, X-linked syndrome.

Fig4. Development and function of regulatory T cells. CD4+ T cells that recognize self antigens may differentiate into regulatory cells in the thymus or peripheral tissues, in a process that is dependent on the transcription factor FoxP3. (The larger arrow from the thymus, compared with the one from peripheral tissues, indicates that most of these cells probably arise in the thymus.) These regulatory cells inhibit the activation of naive T cells and their differentiation into effector T cells by contact-dependent mechanisms or by secreting cytokines that inhibit T cell responses. The generation and maintenance of regulatory T cells also require interleukin-2 (not shown). DC, Dendritic cell; NK, natural killer.

The survival and function of regulatory T cells are dependent on the cytokine IL-2. This role of IL-2 accounts for the severe autoimmune disease that devel ops in mice in which IL-2 or IL-2 receptor genes are deleted and in humans with homozygous mutations in the α or β chain of the IL-2 receptor. Recall that we introduced IL-2 in Chapter 5 as a cytokine made by antigen-activated T cells that stimulates proliferation of these cells. Thus, IL-2 is an example of a cytokine that serves two opposite roles: it promotes immune responses by stimulating T cell proliferation, and it inhibits immune responses by maintaining functional regulatory T cells. Numerous clinical trials are testing the ability of IL-2 to promote regulation and control harmful immune reactions, such as inflammation in autoimmune diseases and graft rejection.

The cytokine transforming growth factor β (TGF β) also plays a role in the generation of regulatory T cells, perhaps by stimulating expression of the FoxP3 transcription factor. Many cell types can produce TGF-β, but the source of TGF-β for inducing regulatory T cells in the thymus or peripheral tissues is not defined.

Regulatory T cells may suppress immune responses by several mechanisms.

• Some regulatory cells produce cytokines (e.g., IL-10, TGF-β) that inhibit the activation of lymphocytes, dendritic cells, and macrophages.

 • Regulatory cells express CTLA-4, which, as dis cussed earlier, may block or remove B7 molecules made by APCs and make these APCs incapable of providing costimulation via CD28 and activating T cells.

• Regulatory T cells, by virtue of the high level of expression of the IL-2 receptor, may bind and consume this essential T cell growth factor, thus reducing its availability for responding T cells.

The great interest in regulatory T cells has in part been driven by the hypothesis that the underlying abnormality in some autoimmune diseases in humans is defective regulatory T cell function or the resistance of pathogenic T cells to regulation. There is also growing interest in cellular therapy with regulatory T cells to treat graft-versus host disease, graft rejection, and autoimmune disorders. 

Deletion: Apoptosis of Mature Lymphocytes

Recognition of self antigens may trigger pathways of apoptosis that result in elimination (deletion) of the self-reactive lymphocytes (Fig. 5). There are two likely mechanisms of death of mature T lymphocytes induced by self antigens:

Fig5. Mechanisms of apoptosis of T lymphocytes. T cells respond to antigen presented by normal anti gen-presenting cells (APCs) by secreting interleukin-2 (IL-2), expressing antiapoptotic (prosurvival) proteins, and undergoing proliferation and differentiation. The antiapoptotic proteins prevent the release of mediators of apoptosis from mitochondria. Self antigen recognition by T cells without costimulation may lead to relative deficiency of intracellular antiapoptotic proteins, and the excess of proapoptotic proteins causes cell death by inducing release of mediators of apoptosis from mitochondria (death by the mitochondrial [intrinsic] path way of apoptosis). Alternatively, self antigen recognition may lead to expression of death receptors and their ligands, such as Fas and Fas ligand (FasL), on lymphocytes, and engagement of the death receptor leads to apoptosis of the cells by the death receptor (extrinsic) pathway.

• Antigen recognition induces in T cells the production of proapoptotic proteins that cause mitochondrial proteins, such as cytochrome c, to leak out and activate cytosolic enzymes called caspases that induce apoptosis. In normal immune responses, the activity of these proapoptotic proteins is counteracted by antiapoptotic proteins that are induced by costimulation and by growth factors produced during the responses. However, self antigens, which are recognized without strong costimulation, do not stimulate production of antiapoptotic proteins, and the relative deficiency of survival signals induces death of the cells that recognize these antigens.

 • Recognition of self antigens may lead to the coexpression of death receptors and their ligands. This ligand- receptor interaction generates signals through the death receptor that culminate in the activation of caspases and apoptosis. The best-defined death receptor–ligand pair involved in self-tolerance is a protein called Fas (CD95), which is expressed on many cell types, and Fas ligand (FasL), which is expressed mainly on activated T cells.

Evidence from genetic studies supports the role of apoptosis in self-tolerance. Eliminating the mitochondrial pathway of apoptosis in mice results in a failure of deletion of self-reactive T cells in the thymus and also in peripheral tissues. Mice with mutations in the fas and fasl genes and children with mutations in FAS all develop autoimmune diseases with lymphocyte accumulation. Children with mutations in the genes encoding caspase-8 or -10, which are downstream of FAS signaling, also have similar autoimmune diseases. The human diseases, collectively called the autoimmune lymphoproliferative syndrome (ALPS), are rare and are the only known examples of defects in apoptosis causing an autoimmune disorder.

From this discussion of the mechanisms of T cell tolerance, it should be clear that self antigens differ from foreign microbial antigens in several ways, which con tribute to the choice between tolerance induced by the former and activation by the latter (Fig. 6).

Fig6. Features of protein antigens that influence the choice between T cell tolerance and activation. This figure summarizes some of the characteristics of self and foreign (e.g., microbial) protein) antigens that determine why the self antigens induce tolerance and microbial antigens stimulate T cell–mediated immune responses. TCR, T cell receptor; Treg, T regulatory cells.

• Self antigens are present in the thymus, where they induce deletion and generate regulatory T cells; by contrast, most microbial antigens tend to be excluded from the thymus because they are typically captured from their sites of entry and transported into peripheral lymphoid organs .

• Self antigens are displayed by resting (costimulator- deficient) APCs in the absence of innate immunity, thus favoring the induction of T cell anergy or death, or suppression by regulatory T cells. By contrast, microbes elicit innate immune reactions, leading to the expression of costimulators and cytokines that promote T cell proliferation and differentiation into effector cells.

 • Self antigens are present throughout life and may therefore cause prolonged or repeated TCR engagement, again promoting anergy, apoptosis, and the development of regulatory T cells. 

مواضيع ذات صلة

الحساسية الدوائية نحو العوامل المخصرة للوصل العَصَبِي العَضَلِي

آليات حساسية السلفوناميدات ومظاهرها

Antigen - Antibody Interaction: Specificity and Cross - Reactivity

ANTIBODY SYNTHESIS

Tolerance to Commensal Microbes and Fetal Antigens

B Lymphocyte Tolerance

Immune Memory

B Cells

T Cells

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