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Immunology and Cell Biology (2007) 85, 267–268; doi:10.1038/sj.icb.7100059; published online 17 April 2007

Tolerance and autoimmunity: Entwined pathways lead to immunological tolerance

Ian R van Driel

Correspondence: Associate Professor IR van Driel, Department of Biochemistry and Molecular Biology, Bio21, Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia. E-mail: i.vandriel@unimelb.edu.au

We know a good deal about individual mechanisms of immunological tolerance, such as clonal deletion, immunoregulation and the actions of cytokines, but we still have only a rudimentary idea of how all these pathways fit together to give us the overall balance of a tolerant immune system. The paper by Liston et al.1 provides an example of how deletion and regulation can create equilibrium and how the absence of the cytokine interleukin (IL)-2 can disrupt this balance.

The immune system is poised to attack invaders but is rarely angered by antigens borne by our own tissues. This is because there are numerous mechanisms that tune the specificity and activity of lymphocytes, both as they develop in the primary lymphoid organs and when they populate peripheral organs. To develop successfully in the thymus, a T-cell must be able to engage major histocompatibility complex (MHC)/peptide with its T-cell antigen receptor (TCR). However, if the avidity of this interaction is too high, then these potentially potent mediators of autoimmune disease receive a death signal and are deleted from the repertoire. Regulatory T cells (Treg cells) also develop in the thymus and it appears that these cells are less susceptible to clonal deletion.2, 3 Treg cells play a vital role in the immune system in preventing unwanted immune responses, such as those against self-antigens.4, 5

Liston et al. provide an example of how thymic selection processes may lead to a balance between effector and regulatory cells. They exploit a system in which almost all T cells in a mouse line express a TCR that recognizes the model antigen hen egg lysozyme (HEL) with high affinity. If these mice also express HEL under the control of the insulin gene regulatory sequences so that HEL is found in the pancreatic beta-cells, which is the cell targeted in autoimmune diabetes, then, somewhat surprisingly, these 'TCR insHEL' mice only develop diabetes at a low incidence. This is despite that fact that almost all the T cells in this mouse are potentially diabetogenic.

Previously, this group had demonstrated that protection from diabetes was in part because HEL is also expressed in the thymus, which induces thymic tolerance to HEL.6 The insulin gene, and thus HEL in this case, is expressed at low levels in the thymus owing to the actions of the aire protein, which promiscuously activates the transcription of a large number of genes that are primarily expressed in extrathymic tissues.3 This promiscuous expression promotes clonal deletion (see Figure 1). Thymic expression of HEL results in clonal deletion of T cells expressing high levels of TCR, leaving relatively low-affinity T cells with low TCR levels to exit the thymus. These low-affinity cells cause pancreatic inflammation, but this condition rarely develops into islet beta-cell destruction and clinically apparent diabetes. The current paper also shows that the cells that survive thymic selection are enriched in HEL-specific Treg cells because of the relative resistance of Treg cells to clonal deletion compared with effector T cells. These Treg cells are likely to suppress the low-affinity HEL-specific effectors and prevent diabetes.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

(a) Thymic selection of self-reactive effector (Teff) and regulatory T cells (Treg) based on the results of Liston et al.1, 3, 6 Left panel: the product of the Aire gene drives expression of self-antigens in thymic epithelial cells resulting in clonal deletion of high-affinity T cells.3, 6 Deletion is not dependent on the presence of IL-2.1 Right panel: the accumulation of Treg in the thymus is partially dependent on IL-2. In the presence of IL-2 fewer high-affinity self-reactive Treg cells survive.1 (b) A model for selection of cells specific for a self-antigen on exposure to antigen in the periphery. Teff (blue) and Treg (red) cells that exit the thymus have overlapping specificities. Engagement of antigen results in the deletion of high-affinity effector cells. Exposure of Treg cells to antigen increases their ability to suppress autoreactive T cells,14 perhaps by the maintenance or expansion of thymically derived Treg cells or the generation of antigen-specific Treg cells from naïve T cells. The overall effect of these events is a population of T cells that is balanced in favour of regulation.

Full figure and legend (73K)

So how does IL-2 fit into this story? IL-2 appears to be a contributing player to the development of autoimmune disease as both the IL-2 and the IL-2 receptor genes have been linked to autoimmune diabetes in mice and humans.7, 8 However, exactly how IL-2 contributes to diabetes is far from clear. Liston et al.1 present here that IL-2 deficiency greatly compromises the accumulation of pancreas-specific Treg cells in the thymus, which leads to a decreased proportion of Treg cells in the periphery and the unleashing of the low-affinity pancreatic islet-specific T cells to cause islet beta-cell destruction and diabetes.

The pathways involved in the development of Treg cells, and the role of IL-2 in this process has received a significant amount of attention. Most recent data suggests that IL-2 is largely but not totally dispensable in the thymic development of Treg cells.9, 10 In IL-2-deficient mice, the number of thymic Treg cells is reduced by up to twofold.10 The paper by Liston et al., in combination with previous data,9 suggests that dependence of certain Treg cells on IL-2 may be a function of the strength of TCR engagement with antigen. Liston et al. demonstrate that the absence of IL-2 leads to depletion of Treg cells with the highest TCR levels and thus avidity for antigen, whereas the Treg cells with lower TCR levels are spared. This is a tantalising finding because it suggests that IL-2 may encourage the development of Treg cells with high avidity for self, which are likely to be more effective at preventing autoimmune disease.11 Of course, further confirmation of this result in systems of wider TCR specificity is required.

The work of Liston et al. emphasizes that the exposure to self-antigen can result in a shift in the balance of pathogenic effector T cells and regulatory T cells. The conditions that result in thymic deletion of high-affinity autoreactive cells may also lead to a more favourable proportion of highly effective Treg cells. It has been suggested that high-avidity interactions with antigen in the thymus can promote the differentiation of Treg cells,12 although this view is not universally held.2 Tweaking of effector and regulatory T-cell populations also occurs in the periphery. Exposure to self-antigen in the extrathymic tissues also leads to deletion of high-affinity self-reactive T cells (see Figure 1).13 The Treg repertoire can also be shaped by events in the periphery. This is probably due to a combination of de novo generation of Treg cells from mature naïve T cells as well as selection of Treg cells by antigen engagement.14 Hence, contact with antigen in the periphery is able to reinforce a balance between suppressor and effector T cells by maintaining Treg cells, and coincidentally silencing the most autoaggressive effector T cells.

Liston et al. also demonstrate in a specific system that the balance of effector and regulatory cells may be disrupted by IL-2 deficiency. Certainly, other factors influence the generation of Treg in the thymus including other cytokines that use CD132 (the common italic gamma-chain) as part of their receptor,15 and CD28 signaling.16 IL-2,9, 10 CD2816 and also TGFbeta17 play significant roles in the maintenance and generation of Treg in the periphery. So, determining the overall balance between Treg and effector cells involves input from several quarters. It remains to be determined which of these pathways will be most amenable to manipulation so that the imbalances that cause autoimmune disease can be rectified.

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References

  1. Liston A, Siggs O, Goodnow CC. Tracing the action of IL-2 in tolerance to islet-specific antigen. Immunol Cell Biol [E-pub ahead of print: 20 March 2007; doi:10.1038/sj.icb.7100049]. | Article |
  2. van Santen HM, Benoist C, Mathis D. Number of T Reg cells that differentiate does not increase upon encounter of agonist ligand on thymic epithelial cells. J Exp Med 2004; 200: 1221–1230. | Article | PubMed | ISI | ChemPort |
  3. Liston A, Gray DH, Lesage S, Fletcher AL, Wilson J, Webster KE et al. Gene dosage-limiting role of aire in thymic expression, clonal deletion, and organ-specific autoimmunity. J Exp Med 2004; 200: 1015–1026. | Article | PubMed | ISI | ChemPort |
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  6. Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC. Aire regulates negative selection of organ-specific T cells. Nat Immunol 2003; 4: 350–354. | Article | PubMed | ISI | ChemPort |
  7. Vella A, Cooper JD, Lowe CE, Walker N, Nutland S, Widmer B et al. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am J Hum Genet 2005; 76: 773–779. | Article | PubMed | ISI | ChemPort |
  8. Lyons PA, Armitage N, Argentina F, Denny P, Hill NJ, Lord CJ et al. Congenic mapping of the type 1 diabetes locus, ldd3, to a 780-kb region of mouse chromosome 3: Identification of a candidate segment of ancestral DNA by haplotype mapping. Genome Res 2000; 10: 446–453. | Article | PubMed | ISI | ChemPort |
  9. D'Cruz LM, Klein L. Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat Immunol 2005; 6: 1152–1159. | Article | PubMed | ChemPort |
  10. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 2005; 6: 1142–1151. | Article | PubMed | ISI | ChemPort |
  11. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 2004; 199: 1455–1465. | Article | PubMed | ISI | ChemPort |
  12. Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Holenbeck AE, Lerman MA et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol 2001; 2: 301–306. | Article | PubMed | ISI | ChemPort |
  13. Davey GM, Kurts C, Miller JF, Bouillet P, Strasser A, Brooks AG et al. Peripheral deletion of autoreactive CD8T cells by cross presentation of self-antigen occurs by a Bcl-2-inhibitable pathway mediated by Bim. J Exp Med 2002; 196: 947–955. | Article | PubMed | ISI | ChemPort |
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  15. Malek TR, Yu A, Vincek V, Scibelli P, Kong L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity 2002; 17: 167–178. | Article | PubMed | ISI | ChemPort |
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