Immune Tolerance

First Printed in R&D Systems 2003 Catalog

Contents

Introduction

A properly functioning immune system mounts immune responses to foreign molecules while remaining tolerant to molecules produced by the host.

Breakdowns in immune tolerance may lead to autoimmunity.
View Larger Image 		Figure 1. Breakdowns in immune tolerance may lead to autoimmunity. Panel A represents weak T cell stimulation by self peptide-MHC normally promotes homeostatic survival and maintenance of the naïve T cell. Alteration of T cell homeostasis may lead to development of lymphoproliferative disorders. Further interaction between partially activated T and B cells can then lead to systemic autoimmunity. Panel B represents a resting T cell encountering stimulating self-antigen. Tolerance occurs by deletion or anergy, whereas defective deletion may promote autoimmunity. T cell-dendritic cell interactions may also lead to autoimmunity in cases where the T cell encounters self antigen and is subsequently activated. Panel C represents T cell interaction with foreign antigen. The majority of T cells will mount an appropriate immune response against the foreign antigen. Some T cells, however, may demonstrate weak cross-reactivity with self antigen and thus promote transient autoimmunity. Alternatively, T cells may also strongly cross-react with self antigen resulting in organ-specific autoimmunity. (Note: illustration has been adapted from Ohashi, P. (2002) Nat. Rev. Immunol. 2:427.)

The primary responsibility of the immune system is to protect the host from foreign materials. Immune tolerance is selective in that the immune system disregards molecules native to the host and responds aggressively to remove foreign molecules. Autoimmune diseases are the result of breakdowns in immune tolerance (Figure 1). The development lineages of B cells and T cells contain several checkpoints at which autoreactive cells are blocked from maturation. The immune system maintains control over self/nonself reactivity with functional regulation of mature lymphocytes.

Exposure of B Cells to Antigen

Immature B cells are the earliest cell type in the lineage to express antigen specific B cell receptors (BCR).1, 2, 3, 4 Selection against autoreactive B cells begins at this stage of development and takes place in the bone marrow.5, 6 A functional BCR binds extracellular molecules and initiates antigen specific cytoplasmic signaling.7, 8, 9, 10 If the B cell does not bind antigen, BCR signaling remains at a basal level, and the cell enters the transitional stage for release into the peripheral circulation. If the immature B cell encounters extracellular antigen capable of crosslinking its BCR, it will experience an increase in BCR-mediated signaling accompanied by developmental arrest.11, 12 This indicates that the B cell has responded to an autoantigen and will be blocked from further development. In addition, the B cell will initiate the receptor editing process to produce BCR with new antigen binding specificities. If it cannot alter its BCR effectively, the immature B cell will be deleted by apoptosis to prevent development into an autoreactive mature B cell. Some autoreactive B cell clones escape deletion and enter the peripheral circulation in an anergic state.13 These cells are not responsive to antigen stimulation but potentially can be activated with pathogen-derived ligands that mimic the autoantigen.14

Genetic Recombination and Receptor Editing

Genetic recombination within the immunoglobulin locus is the major source of BCR diversity, as different immunoglobulin variable domain sequences confer different antigen binding specificities to the receptor. The Rag 1 and Rag 2 proteins, which mediate recombination, are up-regulated under conditions when rearrangement of the heavy and light chain sequences is required and down-regulated at other times.15, 16 Once a B cell produces an antigen receptor, it is normally prevented from further rearrangement of the heavy and light chain sequences (allelic exclusion).17 In the process of receptor editing, however, a B cell re-expresses the Rag proteins and then can produce alternate light chain sequences.18, 19, 20, 21, 22 Replacement light chains are paired with the existing heavy chain and the modified BCR is once again subjected to antigen selection. If receptor editing results in a BCR unresponsive to self antigen, the B cell continues along the development pathway.23, 24 If receptor editing results in a different BCR that is still autoreactive, rearrangement of the light chain locus will continue. Autoreactive B cells which cannot re-express their Rag proteins will be deleted by apoptosis.

During B cell development, the B cell receptor (BCR) is able to enter lipid rafts and initiate signaling only upon antigen cross-linking in mature B cells.
View Larger Image 		Figure 2. During B cell development, the B cell receptor (BCR) is able to enter lipid rafts and initiate signaling only upon antigen cross-linking in mature B cells. [Note: illustration has been adapted from Pierce, S.K. (2002) Nat. Rev. 2:96. ]

BCR Signaling

In a resting mature B cell, the BCR associates with the Ig alpha and Ig beta accessory proteins25, 26, 27 and is separated from them following antigen-induced receptor desensitization.28 Adaptor and accessory proteins are associated with distinct regions of the plasma membrane termed lipid rafts (Figure 2).29 The BCR is able to enter lipid rafts and begin signaling only after it has been cross-linked by antigen binding.30 Positive and negative regulating co-receptors also affect access of the BCR to the raft.31, 32 Cross-linking of the BCR with the positive regulators CD19 and CD21 leads to a longer retention time of the BCR in the raft and consequently, prolonged signaling.33, 34 Involvement of negative regulators such as Fc gamma RII, CD22, and PIR-B opposes BCR-mediated signaling.35 BCR adaptor and accessory proteins as well as the positive and negative regulators directly influence B cell maturation and are involved in the development of tolerance.36 Deletion of any of these proteins affects the production of normal B lymphocytes.

Central T Cell Development

During their double positive stage (expressing CD4 and CD8 co-receptors), thymic T cells complete the assembly of their antigen specific T cell receptor (TCR).37, 38, 39 This genetic recombination is similar to that undergone by the B cell receptor and is also mediated by Rag 1 and Rag 2.40, 41 Like B cells, T cells can alter the antigen specificity of their TCR,42,43 although the mechanism and implications for immune tolerance are not as well understood as for BCR editing.

Antigen-Dependent Selection of T cells

T cells are exposed to antigens presented by class I and class II MHC proteins on the surface of thymic epithelial cells and bone marrow-derived dendritic cells.44, 45 There are three possible outcomes of these interactions.

  • Death by neglect will occur if the TCR-MHC-peptide interaction is absent or too weak. This can be caused by aberrant T cell or target cell proteins, or by an inability of the two cell types to make contact for physiological reasons.
  • Active deletion of the T cell takes place if the TCR-MHC-peptide interaction generates a strong signal. This removes T cell clones that react too strongly with host molecules and would pose a risk of autoimmunity.
  • Those T cells that receive intermediate strength signals continue development into more specialized T cell subsets.46, 47, 48, 49

Mature single positive T cells are released from the thymus and enter the peripheral circulation. A certain leakiness in the selection of T cells leads to the presence of some autoreactive cells in the periphery.50, 51, 52 The activity of these cells must be regulated to avoid autoimmune reactions.

Peripheral T cell tolerance can be regulated by antigen presenting cells and the positive and negative regulatory receptors expressed on T cells.
View Larger Image 		Figure 3. Peripheral T cell tolerance can be regulated by antigen presenting cells and the positive and negative regulatory receptors expressed on T cells. The inhibitory signaling of CTLA-4 counteracts stimulatory effects of CD28 ligation. The balance of CD28 and CTLA-4 derived signals is critical to T cell activation and tolerance. (Note: illustration has been adapted from Walker, L.S.K. & A.K. Abbas [2002] Nat. Rev. Immunol. 2:11.)

Peripheral T Cell Tolerance

Control of T cells continues after lymphcytes have exited the thymus and entered the peripheral circulation.53 The activation of peripheral T cells can be blocked through their negative costimulatory molecules.54, 55 Regulatory T cells can effect the functional inactivation of otherwise competent T cells. Access to cognate peptide antigens can be regulated by antigen presenting cells (Figure 3). In addition, altered T cell migration can prevent the activation of fully competent autoreactive clones.56, 57, 58, 59, 60

Signaling in T Cell Activation

The activity of peripheral mature T cells can be modified by positive and negative regulatory receptors.61 CD28 and CTLA-4 expressed on T cells bind to B7 family members expressed on antigen presenting cells (Figure 3).62, 63 Ligation of CD28 by either B7-1 or B7-2 lowers the threshold of TCR signaling needed to induce T cell activation and also increases the effect of that signal.64, 65 Costimulation via CD28 intensifies T cell cytokine responses and promotes T cell expansion and differentiation.66, 67 The stimulatory effects of CD28 ligation are counteracted by the inhibitory signaling of CTLA-4.68 CTLA-4 ligation by B7-1 or B7-2 results in inhibition of TCR and CD28 mediated signals.69, 70, 71 The balance of CD28 and CTLA-4 derived signals is critical to T cell activation and tolerance.

Several more members of the B7-CD28 superfamily have been recently identified and may be potentially involved in the development or maintenance of immune tolerance (see page 2 for a mini-review on the expanding B7 and CD28 superfamily). ICOS is expressed by activated T cells72 but does not bind B7-1 or B7-2.73, 74 Ligation of ICOS by ICOSL helps to prolong T cell proliferation and IL-2 secretion, but does not facilitate initial activation.75, 76 The tissue distribution of ICOS is more widespread than that of CD28 and includes several nonlymphoid tissues.77 PD-1 is expressed by activated T cells, B cells, and myeloid cells,78 a wider distribution than the predominantly T cell-expressed CD28 and CTLA-4. PD-1 engagement by its ligands, PD-L1 or PD-L2,79 inhibits T cell proliferation and reduces cytokine production.80 Another B7 homolog, B7-H3, can be induced on dendritic cells (DC).81 B7-H3 binds to an unidentified protein on activated T cells other than CD28 and CTLA-4.81

Regulatory T Cells

Regulatory, or suppressor, T cells (Treg) do not proliferate in response to antigen binding but prevent the activation of helper and cytotoxic T cells.82, 83, 84 Treg can suppress CD4+ and CD8+ T cell proliferation and the production of effector cytokines regardless of TCR specificity.83, 85 This is mediated, at least in part, by inhibition of IL-2 transcription within the target cell.86 Treg constitutively express CTLA-487 and secrete inhibitory TGF-beta and IL-10.88, 89 Treg activity requires direct contact with the target T cell,86 although the molecular mechanism for suppression is not clear. They may constitute a specialized T cell subset optimized to reduce the activity of autoreactive T cells.90, 91 Regulatory T cells are released from the thymus as CD4+CD25+ cells.92 The demonstration of in vitro Treg generation by a variety of stimuli93, 94 leaves open the possibility that there may be additional in vivo mechanisms for their generation as well.

DC-Mediated Tolerance

Immature DCs continuously sample and present autoantigens to T cells.95, 96 Due to the low expression levels of class I and class II MHC and costimulatory B7 proteins on immature DC, these interactions do not lead to productive immune responses. Instead, the cognate T cells become tolerant to the self antigen.97, 98, 99, 100 Mature DCs express high levels of MHC and costimulatory proteins and are much more potent at activating T cells. Activation of DCs can be accomplished by ligation of their Toll-like receptors by microbial molecules101, 102, 103 or by binding certain self proteins released from necrotic cells.104, 105

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