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PLOS ONE 2009

Glutamic Acid Decarboxylase-Derived Epitopes with Specific Domains Expand CD4+CD25+ Regulatory T Cells

DOI: 10.1371/journal.pone.0007034

Guojiang Chen, Gencheng Han, Jiannan Feng, Jianan Wang, Renxi Wang, Ruonan Xu, Beifen Shen, Jiahua Qian, Yan Li

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Abstract:

Background CD4+CD25+ regulatory T cell (Treg)-based immunotherapy is considered a promising regimen for controlling the progression of autoimmune diabetes. In this study, we tested the hypothesis that the therapeutic effects of Tregs in response to the antigenic epitope stimulation depend on the structural properties of the epitopes used. Methodology/Principal Findings Splenic lymphocytes from nonobese diabetic (NOD) mice were stimulated with different glutamic acid decarboxylase (GAD)-derived epitopes for 7–10 days and the frequency and function of Tregs was analyzed. We found that, although all expanded Tregs showed suppressive functions in vitro, only p524 (GAD524–538)-expanded CD4+CD25+ T cells inhibited diabetes development in the co-transfer models, while p509 (GAD509–528)- or p530 (GAD530–543)-expanded CD4+CD25+ T cells had no such effects. Using computer-guided molecular modeling and docking methods, the differences in structural characteristics of these epitopes and the interaction mode (including binding energy and identified domains in the epitopes) between the above-mentioned epitopes and MHC class II I-Ag7 were analyzed. The theoretical results showed that the epitope p524, which induced protective Tregs, possessed negative surface-electrostatic potential and bound two chains of MHC class II I-Ag7, while the epitopes p509 and p530 which had no such ability exhibited positive surface-electrostatic potential and bound one chain of I-Ag7. Furthermore, p524 bound to I-Ag7 more stably than p509 and p530. Of importance, we hypothesized and subsequently confirmed experimentally that the epitope (GAD570–585, p570), which displayed similar characteristics to p524, was a protective epitope by showing that p570-expanded CD4+CD25+ T cells suppressed the onset of diabetes in NOD mice. Conclusions/Significance These data suggest that molecular modeling-based structural analysis of epitopes may be an instrumental tool for prediction of protective epitopes to expand functional Tregs.

References

[1]	Kaufman DL, Clare-Salzler M, Tian J, Forsthuber T, Ting GS, et al. (1993) Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 366: 69–72.
[2]	Geng L, Solimena M, Flavell RA, Sherwin RS, Hayday AC (1998) Widespread expression of an autoantigen-GAD65 transgene does not tolerize non-obese diabetic mice and can exacerbate disease. Proc Natl Acad Sci USA 95: 10055–10060.
[3]	Ellis TM, Atkinson MA (1996) The clinical significance of an autoimmune response against glutamic acid decarboxylase. Nat Med 2: 148–153.
[4]	Tisch R, Yang XD, Singer SM, Liblau RS, Fugger L, et al. (1993) Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 366: 72–75.
[5]	Atkinson MA, Kaufman DL, Campbell L, Gibbs KA, Shah SC, et al. (1992) Response of peripheral blood mononuclear cells to glutamate decarboxylase in insulin-dependent diabetes. Lancet 339: 458–459.
[6]	Yoon JW, Yoon CS, Lim HW, Huang QQ, Kang Y, et al. (1999) Control of autoimmune diabetes in NOD mice by GAD expression or suppression in β cells. Science 284: 1183–1187.
[7]	Di Lorenzo TP, Peakman M, Roep BO (2007) Translational mini-review series on type 1 diabetes: Systematic analysis of T cell epitopes in autoimmune diabetes. Clin Exp Immunol 148: 1–16.
[8]	Tian J, Atkinson MA, Clare-Salzler M, Herschenfeld A, Forsthuber T, et al. (1996) Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes. J Exp Med 183: 1561–1567.
[9]	Quinn A, McInerney B, Reich EP, Kim O, Jensen KP, et al. (2001) Regulatory and effector CD4 T cells in nonobese diabetic mice recognize overlapping determinants on glutamic acid decarboxylase and use distinct V β genes. J Immunol 166: 2982–2991.
[10]	Tisch R, Liblau RS, Yang XD, Liblau P, McDevitt HO (1998) Induction of GAD65-specific regulatory T-cells inhibits ongoing autoimmune diabetes in nonobese diabetic mice. Diabetes 47: 894–899.
[11]	Chen C, Lee WH, Yun P, Snow P, Liu CP (2003) Induction of autoantigen-specific Th2 and Tr1 cells and modulation of autoimmune diabetes. J Immunol 171: 733–744.
[12]	Sakaguchi S (2004) Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22: 531–562.
[13]	Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM (2004) CD25+CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 199: 1467–1477.
[14]	Han G, Li Y, Wang J, Wang R, Chen G, et al. (2005) Active tolerance induction and prevention of autoimmune diabetes by immunogene therapy using recombinant adenoassociated virus expressing glutamic acid decarboxylase 65 peptide GAD500–585. J Immunol 174: 4516–4524.
[15]	Zhao Y, Li H, Hou Y, Cha L, Cao Y, et al. (2008) Construction of two mathematical models for prediction of bacterial sRNA targets. Biochem Biophys Res Commun 372: 346–350.
[16]	Hopp TP, Woods KR (1981) Prediction of protein antigenic determinants from amino acid sequences. Proc Natl Acad Sci USA 78: 3824–3828.
[17]	Garnier J, Gibrat JF, Robson B (1996) GOR method for predicting protein secondary structure from amino acid sequence. Methods Enzymol 266: 540–553.
[18]	Welling GW, Weijer WJ, van der Zee R, Welling-Wester S (1985) Prediction of sequential antigenic regions in proteins. FEBS Lett 188: 215–218.
[19]	Janin J (1979) Surface and inside volumes in globular proteins. Nature 277: 491–492.
[20]	Fanelli F, Menziani C, Scheer A, Cotecchia S, De Benedetti PG (1998) Ab initio modeling and molecular simulation of the α 1b-adrenergic receptor activation. Methods 14: 302–317.
[21]	Ortiz AR, Kolinski A, Rotkiewicz P, Ilkowski B, Skolnick J (1999) Ab initio folding of proteins using restraints derived from evolutionary information. Proteins Suppl 3: 177–185.
[22]	Song L, Wang J, Wang R, Yu M, Sun Y, et al. (2004) Retroviral delivery of GAD-IgG fusion construct induces tolerance and modulates diabetes: a role for CD4+ regulatory T cells and TGF-β? Gene Ther 11: 1487–1496.
[23]	Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299: 1057–1061.
[24]	Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4: 330–336.
[25]	Zheng Y, Rudensky AY (2007) Foxp3 in control of the regulatory T cell lineage. Nat Immunol 8: 457–462.
[26]	Salomon B, Bluestone JA (2001) Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol 19: 225–252.
[27]	Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S (2002) Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3: 135–142.
[28]	Herman AE, Freeman GJ, Mathis D, Benoist C (2004) CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J Exp Med 199: 1479–1489.
[29]	Huang CT, Workman CJ, Flies D, Pan X, Marson AL, et al. (2004) Role of LAG-3 in regulatory T cells. Immunity 21: 503–513.
[30]	Yamanouchi J, Rainbow D, Serra P, Howlett S, Hunter K, et al. (2007) Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat Genet 39: 329–337.
[31]	Bayer AL, Yu A, Malek TR (2007) Function of the IL-2R for thymic and peripheral CD4+CD25+ Foxp3+ T regulatory cells. J Immunol 178: 4062–4071.
[32]	Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, et al. (2004) In vitro-expanded autoantigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 199: 1455–1465.
[33]	Barthlott T, Kassiotis G, Stockinger B (2003) T cell regulation as a side effect of homeostasis and competition. J Exp Med 197: 451–460.
[34]	Stockinger B, Barthlott T, Kassiotis G (2001) T cell regulation: a special job or everyone's responsibility? Nat Immunol 2: 757–758.
[35]	Pop SM, Wong CP, Culton DA, Clarke SH, Tisch R (2005) Single cell analysis shows decreasing FoxP3 and TGF-β1 coexpressing CD4+CD25+ regulatory T cells during autoimmune diabetes. J Exp Med 201: 1333–1346.
[36]	Kukreja A, Cost G, Marker J, Zhang C, Sun Z, et al. (2002) Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest 109: 131–140.
[37]	Chen Z, Benoist C, Mathis D (2005) How defects in central tolerance impinge on a deficiency in regulatory T cells. Proc Natl Acad Sci USA 102: 14735–14740.
[38]	Masteller EL, Warner MR, Tang Q, Tarbell KV, McDevitt H, et al. (2005) Expansion of functional endogenous antigen-specific CD4+CD25+ regulatory T cells from nonobese diabetic mice. J Immunol 175: 3053–3059.
[39]	Tarbell KV, Petit L, Zuo X, Toy P, Luo X, et al. (2007) Dendritic cell-expanded, islet-specific CD4+CD25+CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J Exp Med 204: 191–201.
[40]	Dai YD, Jensen KP, Marrero I, Li N, Quinn A, et al. (2008) N-terminal flanking residues of a diabetes-associated GAD65 determinant are necessary for activation of antigen-specific T cells in diabetes-resistant mice. Eur J Immunol 38: 968–976.
[41]	Tarbell KV, Lee M, Ranheim E, Chao CC, Sanna M, et al. (2002) CD4+ T cells from glutamic acid decarboxylase (GAD)65-specific T cells receptor transgenic mice are not diabetogenic and can delay diabetes transfer. J Exp Med 196: 481–492.
[42]	Fisson S, Djelti F, Trenado A, Billiard F, Liblau R, et al. (2006) Therapeutic potential of self-antigen-specific CD4+CD25+ regulatory T cells selected in vitro from a polyclonal repertoire. Eur J Immunol 36: 817–827.
[43]	Ochoa-Repáraz J, Riccardi C, Rynda A, Jun S, Callis G, et al. (2007) Regulatory T cell vaccination without autoantigen protects against experimental autoimmune encephalomyelitis. J Immunol 178: 1791–1799.
[44]	Bommireddy R, Doetschman T (2007) TGF-β1 and Treg cell: alliance for tolerance. Trends Mol Med 13: 492–501.
[45]	Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, et al. (2006) Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 212: 28–50.
[46]	Deng L, Langley RJ, Brown PH, Xu G, Teng L, et al. (2007) Structural basis for the recognition of mutant self by a tumor-specific, MHC class II-restricted T cell receptor, Nat Immunol 8: 398–408.
[47]	Nicholson MJ, Hahn M, Wucherpfennig KM (2005) Unusual features of self-peptide/MHC binding by autoimmune T cell receptors, Immunity 23: 351–360.
[48]	Arneson LS, Peterson M, Sant AJ (2000) The MHC class II molecule I-Ag7 exists in alternate conformations that are peptide dependent. J Immunol 165: 2059–2067.
[49]	Corper AL, Stratmann T, Apostolopoulos V, Scott CA, Garcia KC, et al. (2000) A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes. Science 288: 505–511.
[50]	Zekzer D, Wong FS, Ayalon O, Millet I, Altieri M, et al. (1998) GAD-reactive CD4+ Th1 cells induce diabetes in NOD/SCID mice. J Clin Invest 101: 68–73.
[51]	Severe S, Gauvrit A, Vu AT, Bach JM (2007) CD8+ T lymphocytes specific for glutamic acid decarboxylase 90–98 epitope mediate diabetes in NOD/SCID mouse. Mol Immunol 44: 2950–2960.

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