Entwined pathways lead to immunological tolerance

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  • 1. Immunology and Cell Biology (2007) 85, 267–268 & 2007 Australasian Society for Immunology Inc. All rights reserved 0818-9641/07 $30.00 www.nature.com/icb NEWS AND COMMENTARY Tolerance and autoimmunity Entwined pathways lead to immunological tolerance Ian R van Driel Immunology and Cell Biology (2007) 85, 267–268; doi:10.1038/sj.icb.7100059; published online 17 April 2007 which induces thymic tolerance to HEL.6 The W e know a good deal about individual mechanisms of immunological toler- ance, such as clonal deletion, immunoregula- found in the pancreatic b-cells, which is the cell targeted in autoimmune diabetes, then, somewhat surprisingly, these ‘TCR insHEL’ insulin gene, and thus HEL in this case, is expressed at low levels in the thymus owing tion and the actions of cytokines, but we still mice only develop diabetes at a low incidence. to the actions of the aire protein, which have only a rudimentary idea of how all these This is despite that fact that almost all the T promiscuously activates the transcription of pathways fit together to give us the overall cells in this mouse are potentially diabetogenic. a large number of genes that are primarily balance of a tolerant immune system. The Previously, this group had demonstrated expressed in extrathymic tissues.3 This pro- paper by Liston et al.1 provides an example of that protection from diabetes was in part miscuous expression promotes clonal dele- how deletion and regulation can create equi- because HEL is also expressed in the thymus, tion (see Figure 1). Thymic expression of librium and how the absence of the cytokine interleukin (IL)-2 can disrupt this balance. The immune system is poised to attack a Self - reactive Teff Self - reactive Treg invaders but is rarely angered by antigens -Aire borne by our own tissues. This is because +IL2 Number of T cells there are numerous mechanisms that tune +Aire Number of T cells ±IL2 -IL2 the specificity and activity of lymphocytes, both as they develop in the primary lym- phoid organs and when they populate per- ipheral 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). How- ever, if the avidity of this interaction is too Affinity Affinity high, then these potentially potent mediators of autoimmune disease receive a death signal b Self - reactive Tcells and are deleted from the repertoire. Regula- Prior to selection tory T cells (Treg cells) also develop in the Number of T cells thymus and it appears that these cells are less After selection susceptible to clonal deletion.2,3 Treg cells play a vital role in the immune system in prevent- ing 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 Activity cells in a mouse line express a TCR that recog- Figure 1 (a) Thymic selection of self-reactive effector (Teff) and regulatory T cells (Treg) based on the nizes the model antigen hen egg lysozyme results of Liston et al.1,3,6 Left panel: the product of the Aire gene drives expression of self-antigens in (HEL) with high affinity. If these mice also thymic epithelial cells resulting in clonal deletion of high-affinity T cells.3,6 Deletion is not dependent express HEL under the control of the insulin on the presence of IL-2.1 Right panel: the accumulation of Treg in the thymus is partially dependent on gene regulatory sequences so that HEL is 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 Associate Professor IR van Driel is at the Department of Biochemistry and Molecular Biology, Bio21, Molecular deletion of high-affinity effector cells. Exposure of Treg cells to antigen increases their ability to Science and Biotechnology Institute, University of suppress autoreactive T cells,14 perhaps by the maintenance or expansion of thymically derived Treg Melbourne, Melbourne, Victoria, Australia. ¨ cells or the generation of antigen-specific Treg cells from naıve T cells. The overall effect of these events E-mail: i.vandriel@unimelb.edu.au is a population of T cells that is balanced in favour of regulation.
  • 2. News and Commentary 268 HEL results in clonal deletion of T cells this result in systems of wider TCR specificity 2 van Santen HM, Benoist C, Mathis D. Number of T Reg expressing high levels of TCR, leaving rela- is required. cells that differentiate does not increase upon encoun- ter of agonist ligand on thymic epithelial cells. J Exp tively low-affinity T cells with low TCR levels The work of Liston et al. emphasizes that Med 2004; 200: 1221–1230. to exit the thymus. These low-affinity cells the exposure to self-antigen can result in a 3 Liston A, Gray DH, Lesage S, Fletcher AL, Wilson J, cause pancreatic inflammation, but this con- shift in the balance of pathogenic effector T Webster KE et al. Gene dosage-limiting role of aire in thymic expression, clonal deletion, and organ-specific dition rarely develops into islet b-cell destruc- cells and regulatory T cells. The conditions autoimmunity. J Exp Med 2004; 200: 1015–1026. tion and clinically apparent diabetes. The that result in thymic deletion of high-affinity 4 Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, current paper also shows that the cells that autoreactive cells may also lead to a more Fehervari Z et al. Foxp3+CD25+CD4+ natural regula- tory T cells in dominant self-tolerance and autoimmune survive thymic selection are enriched in HEL- favourable proportion of highly effective Treg disease. Immunolog Rev 2006; 212: 8–27. specific Treg cells because of the relative resis- cells. It has been suggested that high-avidity 5 Zwar TD, van Driel IR, Gleeson PA. Guarding the tance of Treg cells to clonal deletion compared interactions with antigen in the thymus can immune system: suppression of autoimmunity by CD4+CD25+ immunoregulatory T cells. Immunol Cell with effector T cells. These Treg cells are likely promote the differentiation of Treg cells,12 Biol 2006; 84: 487–501. to suppress the low-affinity HEL-specific although this view is not universally held.2 6 Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC. effectors and prevent diabetes. Tweaking of effector and regulatory T-cell Aire regulates negative selection of organ-specific T cells. Nat Immunol 2003; 4: 350–354. So how does IL-2 fit into this story? IL-2 populations also occurs in the periphery. 7 Vella A, Cooper JD, Lowe CE, Walker N, Nutland S, appears to be a contributing player to the Exposure to self-antigen in the extrathymic Widmer B et al. Localization of a type 1 diabetes locus development of autoimmune disease as both tissues also leads to deletion of high-affinity in the IL2RA/CD25 region by use of tag single-nucleo- tide polymorphisms. Am J Hum Genet 2005; 76: 773– the IL-2 and the IL-2 receptor genes have self-reactive T cells (see Figure 1).13 The Treg 779. been linked to autoimmune diabetes in mice repertoire can also be shaped by events in the 8 Lyons PA, Armitage N, Argentina F, Denny P, Hill NJ, and humans.7,8 However, exactly how IL-2 periphery. This is probably due to a combi- Lord CJ et al. Congenic mapping of the type 1 diabetes locus, ldd3, to a 780-kb region of mouse chromosome contributes to diabetes is far from clear. nation of de novo generation of Treg cells from 3: Identification of a candidate segment of ancestral Liston et al.1 present here that IL-2 deficiency ¨ mature naıve T cells as well as selection of Treg DNA by haplotype mapping. Genome Res 2000; 10: greatly compromises the accumulation of cells by antigen engagement.14 Hence, contact 446–453. pancreas-specific Treg cells in the thymus, with antigen in the periphery is able to 9 D’Cruz LM, Klein L. Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in which leads to a decreased proportion of reinforce a balance between suppressor and the absence of interleukin 2 signaling. Nat Immunol Treg cells in the periphery and the unleashing effector T cells by maintaining Treg cells, and 2005; 6: 1152–1159. of the low-affinity pancreatic islet-specific T coincidentally silencing the most autoaggres- 10 Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regula- cells to cause islet b-cell destruction and sive effector T cells. tory T cells. Nat Immunol 2005; 6: 1142–1151. diabetes. Liston et al. also demonstrate in a specific 11 Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J The pathways involved in the development system that the balance of effector and reg- et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 2004; of Treg cells, and the role of IL-2 in this ulatory cells may be disrupted by IL-2 defi- 199: 1455–1465. process has received a significant amount of ciency. Certainly, other factors influence the 12 Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Hole- attention. Most recent data suggests that IL-2 generation of Treg in the thymus including nbeck AE, Lerman MA et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist is largely but not totally dispensable in the other cytokines that use CD132 (the common self-peptide. Nat Immunol 2001; 2: 301–306. thymic development of Treg cells.9,10 In IL-2- g-chain) as part of their receptor,15 and CD28 13 Davey GM, Kurts C, Miller JF, Bouillet P, Strasser A, deficient mice, the number of thymic Treg signaling.16 IL-2,9,10 CD2816 and also TGFb17 Brooks AG et al. Peripheral deletion of autoreactive CD8T cells by cross presentation of self-antigen occurs cells is reduced by up to twofold.10 The play significant roles in the maintenance and by a Bcl-2-inhibitable pathway mediated by Bim. J Exp paper by Liston et al., in combination with generation of Treg in the periphery. So, deter- Med 2002; 196: 947–955. previous data,9 suggests that dependence of mining the overall balance between Treg 14 Samy ET, Setiady YY, Ohno K, Pramoonjago P, Sharp C, Tung KSK. The role of physiological self-antigen in the certain Treg cells on IL-2 may be a function of and effector cells involves input from acquisition and maintenance of regulatory T-cell func- the strength of TCR engagement with anti- several quarters. It remains to be determined tion. Immunolog Rev 2006; 212: 170–184. gen. Liston et al. demonstrate that the which of these pathways will be most 15 Malek TR, Yu A, Vincek V, Scibelli P, Kong L. CD4 regulatory T cells prevent lethal autoimmunity in IL- absence of IL-2 leads to depletion of Treg amenable to manipulation so that the imbal- 2Rbeta-deficient mice. Implications for the nonredun- cells with the highest TCR levels and thus ances that cause autoimmune disease can be dant function of IL-2. Immunity 2002; 17: 167–178. avidity for antigen, whereas the Treg cells with rectified. 16 Tang Q, Henriksen KJ, Boden EK, Tooley AJ, Ye J, Subudhi SK et al. Cutting edge: CD28 controls periph- lower TCR levels are spared. This is a tantalis- eral homeostasis of CD4+CD25+ regulatory T cells. ing finding because it suggests that IL-2 may J Immunol 2003; 171: 3348–3352. encourage the development of Treg cells with 17 Chen W, Jin W, Hardegen N, Lei K-j, Li L, Marinos N et al. Conversion of peripheral CD4+CD25- Naive T high avidity for self, which are likely to be 1 Liston A, Siggs O, Goodnow CC. Tracing the action of Cells to CD4+CD25+ regulatory T cells by tgf-{beta} more effective at preventing autoimmune IL-2 in tolerance to islet-specific antigen. Immunol induction of transcription factor Foxp3. J. Exp. Med. disease.11 Of course, further confirmation of Cell Biol 2007; 85: 338–342 (this issue). 2003; 198: 1875–1886. Immunology and Cell Biology