Skip to main content

Advertisement

SpringerLink
Log in

Manipulating Antigenic Ligand Strength to Selectively Target Myelin-Reactive CD4+ T Cells in EAE

  • Invited Review
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

The development of antigen-specific therapies for the selective tolerization of autoreactive T cells remains the Holy Grail for the treatment of T-cell-mediated autoimmune diseases such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). This quest remains elusive, however, as the numerous antigen-specific strategies targeting myelin-specific T cells over the years have failed to result in clinical success. In this review, we revisit the antigen-based therapies used in the treatment of myelin-specific CD4+ T cells in the context of the functional avidity and the strength of signal of the encephalitogenic CD4+ T cell repertoire. In light of differences in activation thresholds, we propose that autoreactive T cells are not all equal, and therefore tolerance induction strategies must incorporate ligand strength in order to be successful in treating EAE and ultimately the human disease MS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

AICD:

Antigen-induced cell death

APL:

Altered peptide ligand

EAE:

Experimental autoimmune encephalomyelitis

MHC:

Major histocompatibility complex

MVP:

MHC variant peptide

MS:

Multiple sclerosis

MBP:

Myelin basic protein

MOG:

Myelin oligodendrocyte glycoprotein

PLP:

Proteolipid protein

TCR:

T cell receptor

References

  • Acuto O, Di Bartolo V, Micheli F (2008) Tailoring T-cell receptor signals by proximal negative feedback mechanisms. Nat Rev Immunol 8:699–712

    Article  CAS  PubMed  Google Scholar 

  • Alam SM, Gascoigne NR (1998) Posttranslational regulation of TCR Valpha allelic exclusion during T cell differentiation. J Immunol 160:3883–3890

    CAS  PubMed  Google Scholar 

  • Alexander-Miller MA, Leggatt GR, Berzofsky JA (1996) Selective expansion of high- or low-avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy. Proc Natl Acad Sci U S A 93:4102–4107

    Article  CAS  PubMed  Google Scholar 

  • Altan-Bonnet G, Germain RN (2005) Modeling T cell antigen discrimination based on feedback control of digital ERK responses. PLoS Biology 3:e356

    Article  PubMed  CAS  Google Scholar 

  • Anderson AC, Nicholson LB, Legge KL, Turchin V, Zaghouani H, Kuchroo VK (2000) High frequency of autoreactive myelin proteolipid protein-specific T cells in the periphery of naive mice: mechanisms of selection of the self-reactive repertoire. J Exp Med 191:761–770

    Article  CAS  PubMed  Google Scholar 

  • Anderton SM (2001) Peptide-based immunotherapy of autoimmunity: a path of puzzles, paradoxes and possibilities. Immunology 104:367–376

    Article  CAS  PubMed  Google Scholar 

  • Anderton SM (2006) Avoiding autoimmune disease—T cells know their limits. Trends Immunol 27:208–214

    Article  CAS  PubMed  Google Scholar 

  • Anderton SM, Wraith DC (2002) Selection and fine-tuning of the autoimmune T-cell repertoire. Nat Rev Immunol 2:487–498

    Article  CAS  PubMed  Google Scholar 

  • Anderton SM, Manickasingham SP, Burkhart C, Luckcuck TA, Holland SJ, Lamont AG, Wraith DC (1998) Fine specificity of the myelin-reactive T cell repertoire: implications for TCR antagonism in autoimmunity. J Immunol 161:3357–3364

    CAS  PubMed  Google Scholar 

  • Anderton SM, Kissler S, Lamont AG, Wraith DC (1999) Therapeutic potential of TCR antagonists is determined by their ability to modulate a diverse repertoire of autoreactive T cells. Eur J Immunol 29:1850–1857

    Article  CAS  PubMed  Google Scholar 

  • Anderton SM, Radu CG, Lowrey PA, Ward ES, Wraith DC (2001) Negative selection during the peripheral immune response to antigen. J Exp Med 193:1–11

    Article  CAS  PubMed  Google Scholar 

  • Ben-Nun A, Kerlero de Rosbo N, Kaushansky N, Eisenstein M, Cohen L, Kaye JF, Mendel I (2006) Anatomy of T cell autoimmunity to myelin oligodendrocyte glycoprotein (MOG): prime role of MOG44F in selection and control of MOG-reactive T cells in H-2b mice. Eur J Immunol 36:478–493

    Article  CAS  PubMed  Google Scholar 

  • Bielekova B, Goodwin B, Richert N, Cortese I, Kondo T, Afshar G, Gran B, Eaton J, Antel J, Frank JA et al (2000) Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat Med 6:1167–1175

    Article  CAS  PubMed  Google Scholar 

  • Bischof F, Hofmann M, Schumacher TN, Vyth-Dreese FA, Weissert R, Schild H, Kruisbeek AM, Melms A (2004) Analysis of autoreactive CD4 T cells in experimental autoimmune encephalomyelitis after primary and secondary challenge using MHC class II tetramers. J Immunol 172:2878–2884

    CAS  PubMed  Google Scholar 

  • Bouneaud C, Kourilsky P, Bousso P (2000) Impact of negative selection on the T cell repertoire reactive to a self-peptide: a large fraction of T cell clones escapes clonal deletion. Immunity 13:829–840

    Article  CAS  PubMed  Google Scholar 

  • Brocke S, Gijbels K, Allegretta M, Ferber I, Piercy C, Blankenstein T, Martin R, Utz U, Karin N, Mitchell D et al (1996) Treatment of experimental encephalomyelitis with a peptide analogue of myelin basic protein. Nature 379:343–346

    Article  CAS  PubMed  Google Scholar 

  • Carter JD, Neel BG, Lorenz U (1999) The tyrosine phosphatase SHP-1 influences thymocyte selection by setting TCR signaling thresholds. Int Immunol 11:1999–2014

    Article  CAS  PubMed  Google Scholar 

  • Chan C, Stark J, George AJ (2004) Feedback control of T-cell receptor activation. Proc Biol Sci 271:931–939

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Inobe J, Kuchroo VK, Baron JL, Janeway CA Jr, Weiner HL (1996) Oral tolerance in myelin basic protein T-cell receptor transgenic mice: suppression of autoimmune encephalomyelitis and dose-dependent induction of regulatory cells. Proc Natl Acad Sci U S A 93:388–391

    Article  CAS  PubMed  Google Scholar 

  • Christophi GP, Hudson CA, Gruber RC, Christophi CP, Mihai C, Mejico LJ, Jubelt B, Massa PT (2008) SHP-1 deficiency and increased inflammatory gene expression in PBMCs of multiple sclerosis patients. Lab Invest 88:243–255

    Article  CAS  PubMed  Google Scholar 

  • Christophi GP, Panos M, Hudson CA, Tsikkou C, Mihai C, Mejico LJ, Jubelt B, Massa PT (2009) Interferon-beta treatment in multiple sclerosis attenuates inflammatory gene expression through inducible activity of the phosphatase SHP-1. Clin Immunol 133:27–44

    Article  CAS  PubMed  Google Scholar 

  • Cole DK, Pumphrey NJ, Boulter JM, Sami M, Bell JI, Gostick E, Price DA, Gao GF, Sewell AK, Jakobsen BK (2007) Human TCR-binding affinity is governed by MHC class restriction. J Immunol 178:5727–5734

    CAS  PubMed  Google Scholar 

  • Crawford F, Kozono H, White J, Marrack P, Kappler J (1998) Detection of antigen-specific T cells with multivalent soluble class II MHC covalent peptide complexes. Immunity 8:675–682

    Article  CAS  PubMed  Google Scholar 

  • Critchfield JM, Lenardo MJ (1995) Antigen-induced programmed T cell death as a new approach to immune therapy. Clin Immunol Immunopathol 75:13–19

    Article  CAS  PubMed  Google Scholar 

  • Critchfield JM, Racke MK, Zuniga-Pflucker JC, Cannella B, Raine CS, Goverman J, Lenardo MJ (1994) T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis. Science 263:1139–1143

    Article  CAS  PubMed  Google Scholar 

  • Davis MM, Boniface JJ, Reich Z, Lyons D, Hampl J, Arden B, Chien Y (1998) Ligand recognition by alpha beta T cell receptors. Annu Rev Immunol 16:523–544

    Article  CAS  PubMed  Google Scholar 

  • Davis MM, Krogsgaard M, Huse M, Huppa J, Lillemeier BF, Li QJ (2007) T cells as a self-referential, sensory organ. Annu Rev Immunol 25:681–695

    Article  CAS  PubMed  Google Scholar 

  • De Magistris MT, Alexander J, Coggeshall M, Altman A, Gaeta FCA, Grey HM, Sette A (1992) Antigen analog-major histocompatibility complexes act as antagonists of the T cell receptor. Cell 68:625–634

    Article  PubMed  Google Scholar 

  • de Visser KE, Cordaro TA, Kioussis D, Haanen JBAG, Schurnacher NM, Kruisbeek AM (2000) Tracing and characterization of the low-avidity self-specific T cell repertoire. Eur J Immunol 30:1458–1468

    Article  PubMed  Google Scholar 

  • Demotz S, Grey HM, Sette A (1990) The minimal number of class II MHC-antigen complexes needed for T cell activation. Science 249:1028–1030

    Article  CAS  PubMed  Google Scholar 

  • Deng C, Minguela A, Hussain RZ, Lovett-Racke AE, Radu C, Ward ES, Racke MK (2002) Expression of the tyrosine phosphatase SRC homology 2 domain-containing protein tyrosine phosphatase 1 determines T cell activation threshold and severity of experimental autoimmune encephalomyelitis. J Immunol 168:4511–4518

    CAS  PubMed  Google Scholar 

  • Egen JG, Allison JP (2002) Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 16:23–35

    Article  CAS  PubMed  Google Scholar 

  • Ernst B, Lee DS, Chang JM, Sprent J, Surh CD (1999) The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11:173–181

    Article  CAS  PubMed  Google Scholar 

  • Evavold BD, Allen PM (1991) Separation of IL-4 production from Th cell proliferation by an altered T cell receptor ligand. Science 252:1308–1310

    Article  CAS  PubMed  Google Scholar 

  • Evavold BD, Sloan-Lancaster J, Allen PM (1993a) Tickling the TCR: selective T-cell functions stimulated by altered peptide ligands. Immunol Today 14:602–609

    Article  CAS  PubMed  Google Scholar 

  • Evavold BD, Sloan-Lancaster J, Hsu BL, Allen PM (1993b) Separation of T helper 1 clone cytolysis from proliferation and lymphokine production using analog peptides. J Immunol 150:3131–3140

    CAS  PubMed  Google Scholar 

  • Evavold BD, Sloan-Lancaster J, Wilson KJ, Rothbard JB, Allen PM (1995) Specific T cell recognition of minimally homologous peptides: evidence for multiple endogenous ligands. Immunity 2:655–663

    Article  CAS  PubMed  Google Scholar 

  • Falk K, Rotzschke O, Stevanovic S, Jung G, Rammensee HG (1991) Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature 351:290–296

    Article  CAS  PubMed  Google Scholar 

  • Falta MT, Fontenot AP, Rosloniec E, Crawford F, Roark CL, Bill J, Marrack P, Kappler J, Kotzin BL (2005) Class II major histocompatibility complex-peptide tetramer staining in relation to functional avidity and T cell receptor diversity in the mouse CD4+ T cell response to a rheumatoid arthritis-associated antigen. Arthritis Rheum 52:1885–1896

    Article  CAS  PubMed  Google Scholar 

  • Fasso M, Anandasabapathy N, Crawford F, Fathman CG, Ridgway WM (2000) T cell receptor (TCR)-mediated repertoire selection and loss of TCR Vbeta diversity during the initiation of a CD4+ T cell response in vivo. J Exp Med 192:1719–1730

    Article  CAS  PubMed  Google Scholar 

  • Feng X, Petraglia AL, Chen M, Byskosh PV, Boos MD, Reder AT (2002) Low expression of interferon-stimulated genes in active multiple sclerosis is linked to subnormal phosphorylation of STAT1. J Neuroimmunol 129:205–215

    Article  CAS  PubMed  Google Scholar 

  • Ford ML, Evavold BD (2003) Regulation of polyclonal T cell responses by an MHC anchor-substituted variant of myelin oligodendrocyte glycoprotein 35–55. J Immunol 171:1247–1254

    CAS  PubMed  Google Scholar 

  • Ford ML, Evavold BD (2004a) An MHC anchor-substituted analog of myelin oligodendrocyte glycoprotein 35–55 induces IFN-gamma and autoantibodies in the absence of experimental autoimmune encephalomyelitis and optic neuritis. Eur J Immunol 34:388–397

    Article  CAS  PubMed  Google Scholar 

  • Ford ML, Evavold BD (2004b) Degenerate recognition of T cell epitopes: impact of T cell receptor reserve and stability of peptide: MHC complexes. Mol Immunol 40:1019–1025

    Article  CAS  PubMed  Google Scholar 

  • Franco A, Southwood S, Arrhenius T, Kuchroo VK, Grey HM, Sette A, Ishioka G (1994) T cell receptor antagonist peptides are highly effective inhibitors of experimental allergic encephalomyelitis. Eur J Immunol 24:940–946

    Article  CAS  PubMed  Google Scholar 

  • Fremont DH, Hendrickson WA, Marrack P, Kappler J (1996) Structures of an MHC class II molecule with covalently bound single peptides. Science 272:1001–1004

    Article  CAS  PubMed  Google Scholar 

  • Garcia KC, Radu CG, Ho J, Ober RJ, Ward ES (2001) Kinetics and thermodynamics of T cell receptor–autoantigen interactions in murine experimental autoimmune encephalomyelitis. Proc Natl Acad Sci 98:6818–6823

    Article  CAS  PubMed  Google Scholar 

  • Gaur A, Boehme SA, Chalmers D, Crowe PD, Pahuja A, Ling N, Brocke S, Steinman L, Conlon PJ (1997) Amelioration of relapsing experimental autoimmune encephalomyelitis with altered myelin basic protein peptides involves different cellular mechanisms. J Neuroimmunol 74:149–158

    Article  CAS  PubMed  Google Scholar 

  • Gebe JA, Falk BA, Rock KA, Kochik SA, Heninger AK, Reijonen H, Kwok WW, Nepom GT (2003) Low-avidity recognition by CD4+ T cells directed to self-antigens. Eur J Immunol 33:1409–1417

    Article  CAS  PubMed  Google Scholar 

  • Genain CP, Abel K, Belmar N, Villinger F, Rosenberg DP, Linington C, Raine CS, Hauser SL (1996) Late complications of immune deviation therapy in a nonhuman primate. Science 274:2054–2057

    Article  CAS  PubMed  Google Scholar 

  • Green MC, Shultz LD (1975) Motheaten, an immunodeficient mutant of the mouse. I. Genetics and pathology. J Hered 66:250–258

    CAS  PubMed  Google Scholar 

  • Gronski MA, Boulter JM, Moskophidis D, Nguyen LT, Holmberg K, Elford AR, Deenick EK, Kim HO, Penninger JM, Odermatt B et al (2004) TCR affinity and negative regulation limit autoimmunity. Nat Med 10:1234–1239

    Article  CAS  PubMed  Google Scholar 

  • Harding CV, Unanue ER (1990) Quantitation of antigen-presenting cell MHC class II/peptide complexes necessary for T-cell stimulation. Nature 346:574–576

    Article  CAS  PubMed  Google Scholar 

  • Harrington CJ, Paez A, Hunkapiller T, Mannikko V, Brabb T, Ahearn M, Beeson C, Goverman J (1998) Differential tolerance is induced in T cells recognizing distinct epitopes of myelin basic protein. Immunity 8:571–580

    Article  CAS  PubMed  Google Scholar 

  • Hemmer B, Fleckenstein BT, Vergelli M, Jung G, McFarland H, Martin RW (1997) Identification of high potency microbial and self ligands for a human autoreactive class II-restricted T cell clone [see comments]. J Exp Med 185:1651–1659

    Article  CAS  PubMed  Google Scholar 

  • Hemmer B, Vergelli M, Gran B, File RSNI, Conlon P, Pinilla C, Houghten R, McFarland HF, Martin R (1998) Predictable TCR antigen recognition based on peptide scans leads to the identification of agonist ligands with no sequence homology. J Immunol 160:3631–3636

    CAS  PubMed  Google Scholar 

  • Hemmer B, Pinilla C, Gran B, Vergelli M, Ling N, Conlon P, McFarland HF, Houghten R, Martin R (2000) Contribution of individual amino acids within MHC molecule or antigenic peptide to TCR ligand potency. J Immunol 164:861–871

    CAS  PubMed  Google Scholar 

  • Irvine DJ, Purbhoo MA, Krogsgaard M, Davis MM (2002) Direct observation of ligand recognition by T cells. Nature 419:845–849

    Article  CAS  PubMed  Google Scholar 

  • Jameson SC, Bevan MJ (1995) T cell receptor antagonists and partial agonists. Immunity 2:1–11

    Article  CAS  PubMed  Google Scholar 

  • Johnson KG, LeRoy FG, Borysiewicz LK, Matthews RJ (1999) TCR signaling thresholds regulating T cell development and activation are dependent upon SHP-1. J Immunol 162:3802–3813

    CAS  PubMed  Google Scholar 

  • Jones DS, Reichardt P, Ford ML, Edwards LJ, Evavold BD (2008) TCR antagonism by peptide requires high TCR expression. J Immunol 181:1760–1766

    CAS  PubMed  Google Scholar 

  • Kappos L, Comi G, Panitch H, Oger J, Antel J, Conlon P, Steinman L (2000) Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial. The Altered Peptide Ligand in Relapsing MS Study Group. Nat Med 6:1176–1182

    Article  CAS  PubMed  Google Scholar 

  • Karin N, Mitchell DJ, Brocke S, Ling N, Steinman L (1994) Reversal of experimental autoimmune encephalomyelitis by a soluble peptide variant of a myelin basic protein epitope: T cell receptor antagonism and reduction of interferon gamma and tumor necrosis factor alpha production. J Exp Med 180:2227–2237

    Article  CAS  PubMed  Google Scholar 

  • Kawamura K, McLaughlin KA, Weissert R, Forsthuber TG (2008) Myelin-reactive type B T cells and T cells specific for low-affinity MHC-binding myelin peptides escape tolerance in HLA-DR transgenic mice. J Immunol 181:3202–3211

    CAS  PubMed  Google Scholar 

  • Kedl RM, Kappler JW, Marrack P (2003) Epitope dominance, competition and T cell affinity maturation. Curr Opin Immunol 15:120–127

    Article  CAS  PubMed  Google Scholar 

  • Kersh GJ, Allen PM (1996) Essential flexibility in the T-cell recognition of antigen. Nature 380:495–498

    Article  CAS  PubMed  Google Scholar 

  • Kersh GJ, Kersh EN, Fremont DH, Allen PM (1998) High- and low-potency ligands with similar affinities for the TCR: the importance of kinetics in TCR signaling. Immunity 9:817–826

    Article  CAS  PubMed  Google Scholar 

  • Kersh GJ, Miley MJ, Nelson CA, Grakoui A, Horvath S, Donermeyer DL, Kappler J, Allen PM, Fremont DH (2001) Structural and functional consequences of altering a peptide MHC anchor residue. J Immunol 166:3345–3354

    CAS  PubMed  Google Scholar 

  • Kilgore NE, Carter JD, Lorenz U, Evavold BD (2003) Cutting edge: dependence of TCR antagonism on Src homology 2 domain-containing protein tyrosine phosphatase activity. J Immunol 170:4891–4895

    CAS  PubMed  Google Scholar 

  • Korb LC, Mirshahidi S, Ramyar K, Akha AAS, Sadegh-Nasseri S (1999) Induction of T cell anergy by low numbers of agonist ligands. J Immunol 162:6401–6409

    CAS  PubMed  Google Scholar 

  • Korn T, Reddy J, Gao W, Bettelli E, Awasthi A, Petersen TR, Backstrom BT, Sobel RA, Wucherpfennig KW, Strom TB et al (2007) Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat Med 3:423–431

    Article  CAS  Google Scholar 

  • Kozlowski M, Mlinaric-Rascan I, Feng GS, Shen R, Pawson T, Siminovitch KA (1993) Expression and catalytic activity of the tyrosine phosphatase PTP1C is severely impaired in motheaten and viable motheaten mice. J Exp Med 178:2157–2163

    Article  CAS  PubMed  Google Scholar 

  • Kuchroo VK, Greer JM, Kaul D, Ishioka G, Franco A, Sette A, Sobel RA, Lees MB (1994) A single TCR antagonist peptide inhibits experimental allergic encephalomyelitis mediated by a diverse T cell repertoire. J Immunol 153:3326–3336

    CAS  PubMed  Google Scholar 

  • Kuchroo VK, Anderson AC, Waldner H, Munder M, Bettelli E, Nicholson LB (2002) T cell response in experimental autoimmune encephalomyelitis (EAE): role of self and cross-reactive antigens in shaping, tuning, and regulating the autopathogenic T cell repertoire. Annu Rev Immunol 20:101–123

    Article  CAS  PubMed  Google Scholar 

  • Lazarski CA, Chaves FA, Jenks SA, Wu S, Richards KA, Weaver JM, Sant AJ (2005) The kinetic stability of MHC class II:peptide complexes is a key parameter that dictates immunodominance. Immunity 23:29–40

    Article  CAS  PubMed  Google Scholar 

  • Li QJ, Chau J, Ebert PJ, Sylvester G, Min H, Liu G, Braich R, Manoharan M, Soutschek J, Skare P et al (2007) miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129:147–161

    Article  CAS  PubMed  Google Scholar 

  • Liblau RS, Tisch R, Shokat K, Yang X, Dumont N, Goodnow CC, McDevitt HO (1996) Intravenous injection of soluble antigen induces thymic and peripheral T-cells apoptosis. Proc Natl Acad Sci U S A 93:3031–3036

    Article  CAS  PubMed  Google Scholar 

  • Liu GY, Fairchild PJ, Smith RM, Prowle JR, Kioussis D, Wraith DC (1995) Low avidity recognition of self-antigen by T cells permits escape from central tolerance. Immunity 3:407–415

    Article  CAS  PubMed  Google Scholar 

  • Lorenz U, Ravichandran KS, Burakoff SJ, Neel BG (1996) Lack of SHPTP1 results in src-family kinase hyperactivation and thymocyte hyperresponsiveness. Proc Natl Acad Sci U S A 93:9624–9629

    Article  CAS  PubMed  Google Scholar 

  • Ma Z, Sharp KA, Janmey PA, Finkel TH (2008) Surface-anchored monomeric agonist pMHCs alone trigger TCR with high sensitivity. PLoS Biol 6:e43

    Article  PubMed  CAS  Google Scholar 

  • Malherbe L, Hausl C, Teyton L, McHeyzer-Williams MG (2004) Clonal selection of helper T cells is determined by an affinity threshold with no further skewing of TCR binding properties. Immunity 21:669–679

    Article  CAS  PubMed  Google Scholar 

  • Mallone R, Kochik SA, Reijonen H, Carson B, Ziegler SF, Kwok WW, Nepom GT (2005) Functional avidity directs T-cell fate in autoreactive CD4+ T cells. Blood 106:2798–2805

    Article  CAS  PubMed  Google Scholar 

  • Margot CD, Ford ML, Evavold BD (2005) Amelioration of established experimental autoimmune encephalomyelitis by an MHC anchor-substituted variant of proteolipid protein 139–151. J Immunol 174:3352–3358

    CAS  PubMed  Google Scholar 

  • Margulies DH (2001) TCR avidity: it’s not how strong you make it, it’s how you make it strong. Nat Immunol 2:669–670

    Article  CAS  PubMed  Google Scholar 

  • Mason D (1998) A very high level of cross reactivity is an essential feature of the T-cell receptor. Immunol Today 19:395–404

    Article  CAS  PubMed  Google Scholar 

  • Matsui K, Boniface JJ, Steffner P, Reay PA, Davis MM (1994) Kinetics of T-cell receptor binding to peptide/I-Ek complexes: correlation of the dissociation rate with T-cell responsiveness. Proc Natl Acad Sci U S A 91:12862–12866

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto Y, Tsuchida M, Hanawa H, Abo T (1994) Successful prevention and treatment of autoimmune encephalomyelitis by short-term administration of anti-T-cell receptor alpha beta antibody. Immunology 81:1–7

    CAS  PubMed  Google Scholar 

  • Matsushita T, Yanaba K, Bouaziz J, Fujimoto M, Tedder TF (2008) Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J Clin Invest 118:3420–3430

    CAS  PubMed  Google Scholar 

  • Mazzanti B, Hemmer B, Traggiai E, Ballerini C, McFarland HF, Massacesi L, Martin R, Vergelli M (2000) Decrypting the spectrum of antigen-specific T-cell responses: the avidity repertoire of MBP-specific T-cells. J Neurosci Res 59:86–93

    Article  CAS  PubMed  Google Scholar 

  • McCue D, Ryan KR, Wraith DC, Anderton SM (2004) Activation thresholds determine susceptibility to peptide-induced tolerance in a heterogeneous myelin-reactive T cell repertoire. J Neuroimmunol 156:96–106

    Article  CAS  PubMed  Google Scholar 

  • McNeil LK, Evavold BD (2002) Dissociation of peripheral T cell responses from thymocyte negative selection by weak agonists supports a spare receptor model of T cell activation. Proc Natl Acad Sci U S A 99:4520–4525

    Article  CAS  PubMed  Google Scholar 

  • McNeil LK, Evavold BD (2003) TCR reserve: a novel principle of CD4 T cell activation by weak ligands. J Immunol 170:1224–1230

    CAS  PubMed  Google Scholar 

  • Mendel I, Kerlero de Rosbo N, Ben-Nun A (1996) Delineation of the minimal encephalitogenic epitope within the immunodominant region of myelin oligodendrocyte glycoprotein: diverse Vβ gene usage by T cells recognizing the core epitope encephalitogenic for T cell receptor V-beta b and T cell receptor V-beta a H-2b mice. Eur J Immunol 26:2470–2479

    Article  CAS  Google Scholar 

  • Mirshahidi S, Huang CT, Sadegh-Nasseri S (2001) Anergy in peripheral memory CD4(+) T cells induced by low avidity engagement of T cell receptor. J Exp Med 194:719–731

    Article  CAS  PubMed  Google Scholar 

  • Munder M, Bettelli E, Monney L, Slavik JM, Nicholson LB, Kuchroo VK (2002) Reduced self-reactivity of an autoreactive T cell after activation with cross-reactive non-self-ligand. J Exp Med 196:1151–1162

    Article  CAS  PubMed  Google Scholar 

  • Muranski P, Chmielowski B, Ignatowicz L (2000) Mature CD4+ T cells perceive a positively selecting class II MHC/peptide complex in the periphery. J Immunol 164:3087–3094

    CAS  PubMed  Google Scholar 

  • Naramura M, Jang IK, Kole H, Huang F, Haines D, Gu H (2002) c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nat Immunol 3:1192–1199

    Article  CAS  PubMed  Google Scholar 

  • Nicholson LB, Greer JM, Sobel RA, Lees MB, Kuchroo VK (1995) An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. Immunity 3:397–405

    Article  CAS  PubMed  Google Scholar 

  • Nicholson LB, Waldner H, Carrizosa AM, Sette A, Collins M, Kuchroo VK (1998) Heteroclitic proliferative responses and changes in cytokine profile induced by altered peptides: implications for autoimmunity. Proc Natl Acad Sci U S A 95:264–269

    Article  CAS  PubMed  Google Scholar 

  • Pearson CI, van Ewijk W, McDevitt HO (1997) Induction of apoptosis and T helper 2 (Th2) responses correlates with peptide affinity for the major histocompatibility complex in self-reactive T cell receptor transgenic mice. J Exp Med 185:583–599

    Article  CAS  PubMed  Google Scholar 

  • Pedotti R, Mitchell D, Wedemeyer J, Karpuj M, Chabas D, Hattab EM, Tsai M, Galli SJ, Steinman L (2001) An unexpected version of horror autotoxicus: anaphylactic shock to a self-peptide. Nat Immunol 2:216–222

    Article  CAS  PubMed  Google Scholar 

  • Price DA, Brenchley JM, Ruff LE, Betts MR, Hill BJ, Roederer M, Koup RA, Migueles SA, Gostick E, Wooldridge L et al (2005) Avidity for antigen shapes clonal dominance in CD8+ T cell populations specific for persistent DNA viruses. J Exp Med 202:1349–1361

    Article  CAS  PubMed  Google Scholar 

  • Radu CG, Anderton SM, Firan M, Wraith DC, Ward ES (2000) Detection of autoreactive T cells in H-2u mice using peptide-MHC multimers. Int Immunol 12:1553–1560

    Article  CAS  PubMed  Google Scholar 

  • Reay PA, Matsui K, Haase K, Wulfing C, Chien YH, Davis MM (2000) Determination of the relationship between T cell responsiveness and the number of MHC-peptide complexes using specific monoclonal antibodies. J Immunol 164:5626–5634

    CAS  PubMed  Google Scholar 

  • Reddy J, Bettelli E, Nicholson L, Waldner H, Jang MH, Wucherpfennig KW, Kuchroo VK (2003) Detection of autoreactive myelin proteolipid protein 139–151-specific T cells by using MHC II (IAs) tetramers. J Immunol 170:870–877

    CAS  PubMed  Google Scholar 

  • Rees W, Bender J, Teague TK, Kedl RM, Crawford F, Marrack P, Kappler J (1999) An inverse relationship between T cell receptor affinity and antigen dose during CD4(+) T cell responses in vivo and in vitro. Proc Natl Acad Sci U S A 96:9781–9786

    Article  CAS  PubMed  Google Scholar 

  • Reichstetter S, Kwok WW, Kochik S, Koelle DM, Beaty JS, Nepom GT (1999) MHC–peptide ligand interactions establish a functional threshold for antigen-specific T cell recognition. Hum Immunol 60:608–618

    Article  CAS  PubMed  Google Scholar 

  • Reichstetter S, Ettinger RA, Liu AW, Gebe JA, Nepom GT, Kwok WW (2000) Distinct T cell interactions with HLA class II tetramers characterize a spectrum of TCR affinities in the human antigen-specific T cell response. J Immunol 165:6994–6998

    CAS  PubMed  Google Scholar 

  • Reijonen H, Novak EJ, Kochik S, Heninger A, Liu AW, Kwok WW, Nepom GT (2002) Detection of GAD65-specific T-cells by major histocompatibility complex class II tetramers in type 1 diabetic patients and at-risk subjects. Diabetes 51:1375–1382

    Article  CAS  PubMed  Google Scholar 

  • Ridgway WM, Fasso M, Fathman CG (1999) A new look at MHC and autoimmune disease. Science 284(749):751

    Google Scholar 

  • Rosette C, Werlen G, Daniels MA, Holman PO, Alam SM, Travers PJ, Gascoigne NR, Palmer E, Jameson SC (2001) The impact of duration versus extent of TCR occupancy on T cell activation: a revision of the kinetic proofreading model. Immunity 15:59–70

    Article  CAS  PubMed  Google Scholar 

  • Rudensky A, Preston-Hurlburt P, al-Ramadi BK, Rothbard J, Janeway CA Jr (1992) Truncation variants of peptides isolated from MHC class II molecules suggest sequence motifs. Nature 359:429–431

    Article  CAS  PubMed  Google Scholar 

  • Ryan KR, Evavold BD (1998) Persistence of peptide-induced CD4+ T cell anergy in vitro. J Exp Med 187:89–96

    Article  CAS  PubMed  Google Scholar 

  • Ryan KR, McNeil LK, Dao C, Jensen PE, Evavold BD (2004) Modification of peptide interaction with MHC creates TCR partial agonists. Cell Immunol 227:70–78

    Article  CAS  PubMed  Google Scholar 

  • Ryan KR, McCue D, Anderton SM (2005) Fas-mediated death and sensory adaptation limit the pathogenic potential of autoreactive T cells after strong antigenic stimulation. J Leukoc Biol 78:43–50

    Article  CAS  PubMed  Google Scholar 

  • Sabatino JJ Jr, Shires J, Altman JD, Ford ML, Evavold BD (2008) Loss of IFN-gamma enables the expansion of autoreactive CD4+ T cells to induce experimental autoimmune encephalomyelitis by a nonencephalitogenic myelin variant antigen. J Immunol 180:4451–4457

    CAS  PubMed  Google Scholar 

  • Samson MF, Smilek DE (1995) Reversal of acute experimental autoimmune encephalomyelitis and prevention of relapses by treatment with a myelin basic protein peptide analogue modified to form long-lived peptide–MHC complexes. J Immunol 155:2737–2746

    CAS  PubMed  Google Scholar 

  • Sandberg JK, Franksson L, Sundback J, Michaelsson J, Petersson M, Achour A, Wallin RPA, Sherman NE, Bergman T, Jornvall H et al (2000) T cell tolerance based on avidity thresholds rather than complete deletion allows maintenance of maximal repertoire diversity. J Immunol 165:25–33

    CAS  PubMed  Google Scholar 

  • Sanjuan MA, Jones DR, Izquierdo M, Merida I (2001) Role of diacylglycerol kinase alpha in the attenuation of receptor signaling. J Cell Biol 153:207–220

    Article  CAS  PubMed  Google Scholar 

  • Savage PA, Boniface JJ, Davis MM (1999) A kinetic basis for T cell receptor repertoire selection during an immune response. Immunity 10:485–492

    Article  CAS  PubMed  Google Scholar 

  • Shultz LD, Coman DR, Bailey CL, Beamer WG, Sidman CL (1984) “Viable motheaten”, a new allele at the motheaten locus. I. Pathology. Am J Pathol 116:179–192

    CAS  PubMed  Google Scholar 

  • Sloan-Lancaster J, Allen PM (1996) Altered peptide ligand-induced partial T cell activation: molecular mechanisms and role in T cell biology. Annu Rev Immunol 14:1–27

    Article  CAS  PubMed  Google Scholar 

  • Smilek DE, Wraith DC, Hodgkinson S, Dwivedy S, Steinman L, McDevitt HO (1991) A single amino acid change in a myelin basic protein peptide confers the capacity to prevent rather than induce experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 88:9633–9637

    Article  CAS  PubMed  Google Scholar 

  • Stefanova I, Dorfman JR, Germain RN (2002) Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes. Nature 420:429–434

    Article  CAS  PubMed  Google Scholar 

  • Stefanova I, Hemmer B, Vergelli M, Martin R, Biddison WE, Germain RN (2003) TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat Immunol 4:248–254

    Article  CAS  PubMed  Google Scholar 

  • Stone JD, Cochran JR, Stern LJ (2001) T-cell activation by soluble MHC oligomers can be described by a two-parameter binding model. Biophys J 81:2547–2557

    Article  CAS  PubMed  Google Scholar 

  • Targoni OS, Lehmann PV (1998) Endogenous myelin basic protein inactivates the high avidity T cell repertoire. J Exp Med 187:2055–2063

    Article  CAS  PubMed  Google Scholar 

  • Vollers SS, Stern LJ (2008) Class II major histocompatibility complex tetramer staining: progress, problems, and prospects. Immunology 123:305–313

    Article  CAS  PubMed  Google Scholar 

  • Walker LS, Abbas AK (2002) The enemy within: keeping self-reactive T cells at bay in the periphery. Nat Rev Immunol 2:11–19

    Article  CAS  PubMed  Google Scholar 

  • Wang R, Wang-Zhu Y, Gabaglia CR, Kimachi K, Grey HM (1999) The stimulation of low-affinity, nontolerized clones by heteroclitic antigen analogues causes the breaking of tolerance established to an immunodominant T cell epitope. J Exp Med 190:983–994

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Gjorloff-Wingren A, Saxena M, Pathan N, Reed JC, Mustelin T (2000) The tumor suppressor PTEN regulates T cell survival and antigen receptor signaling by acting as a phosphatidylinositol 3-phosphatase. J Immunol 164:1934–1939

    CAS  PubMed  Google Scholar 

  • Wasserman HA, Evavold BD (2008) Induction of anergy by antibody blockade of TCR in myelin oligodendrocyte glycoprotein-specific cells. J Immunol 180:7259–7264

    CAS  PubMed  Google Scholar 

  • Wasserman HA, Beal CD, Zhang Y, Jiang N, Zhu C, Evavold BD (2008) MHC variant peptide-mediated anergy of encephalitogenic T cells requires SHP-1. J Immunol 181:6843–6849

    CAS  PubMed  Google Scholar 

  • Wauben MHM, Boog CJP, van der Zee R, Joosten I, Schlief A, van Eden W (1992) Disease inhibition by major histocompatibility complex binding peptide analogues of disease-associated epitopes: more than blocking alone. J Exp Med 176:667–677

    Article  CAS  PubMed  Google Scholar 

  • Whitacre CC, Gienapp IE, Meyer A, Cox KL, Javed N (1996) Treatment of autoimmune disease by oral tolerance to autoantigens. Clin Immunol Immunopathol 80:S31–39

    Article  CAS  PubMed  Google Scholar 

  • Wooldridge L, Lissina A, Cole DK, van den Berg HA, Price DA, Sewell AK (2009) Tricks with tetramers: how to get the most from multimeric peptide–MHC. Immunology 126:147–164

    Article  CAS  PubMed  Google Scholar 

  • Wraith DC, Smilek DE, Mitchell DJ, Steinman L, McDevitt HO (1989) Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy. Cell 59:247–255

    Article  CAS  PubMed  Google Scholar 

  • Wraith DC, Bruun B, Fairchild PJ (1992) Cross-reactive antigen recognition by an encephalitogenic T cell receptor. Implications for T cell biology and autoimmunity. J Immunol 149:3765–3770

    CAS  PubMed  Google Scholar 

  • Zehn D, Bevan MJ (2006) T cells with low avidity for a tissue-restricted antigen routinely evade central and peripheral tolerance and cause autoimmunity. Immunity 25:261–270

    Article  CAS  PubMed  Google Scholar 

  • Zehn D, Lee SY, Bevan MJ (2009) Complete but curtailed T-cell response to very low-affinity antigen. Nature 458:211–214

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Somani AK, Watt S, Mills GB, Siminovitch KA (1999a) The Src-homology domain 2-bearing protein tyrosine phosphatase-1 inhibits antigen receptor-induced apoptosis of activated peripheral T cells. J Immunol 162:6359–6367

    CAS  PubMed  Google Scholar 

  • Zhang J, Somani AK, Yuen D, Yang Y, Love PE, Siminovitch KA (1999b) Involvement of the SHP-1 tyrosine phosphatase in regulation of T cell selection. J Immunol 163:3012–3021

    CAS  PubMed  Google Scholar 

  • Zugel U, Wang R, Shih G, Sette A, Alexander J, Grey HM (1998) Termination of peripheral tolerance to a T cell epitope by heteroclitic antigen analogues. J Immunol 161:1705–1709

    CAS  PubMed  Google Scholar 

Download references

Disclaimer

None

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, Emory University, 1510 Clifton Road, Atlanta, GA, 30322, USA

    Joseph J. Sabatino Jr, Kristen M. Rosenthal & Brian D. Evavold

Authors
  1. Joseph J. Sabatino Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kristen M. Rosenthal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brian D. Evavold
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Brian D. Evavold.

Additional information

This work was supported by grants from the NIH R01 NS062358 and National Multiple Sclerosis Society RG 4047.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sabatino, J.J., Rosenthal, K.M. & Evavold, B.D. Manipulating Antigenic Ligand Strength to Selectively Target Myelin-Reactive CD4+ T Cells in EAE. J Neuroimmune Pharmacol 5, 176–188 (2010). https://doi.org/10.1007/s11481-009-9181-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-009-9181-3

Keywords

Search

Navigation