Advertisement

Dynamic Tuning of T Cell Receptor Specificity by Co-Receptors and Costimulation

Chapter

Abstract

Mounting evidence that each clonotype of T cell antigen receptor can productively interact with hundreds or even thousands of peptide antigens would appear to conflict, prima facie, with the immune system’s primary task of guarding against auto-immunity and singling out harmful “non-self” epitopes against a background of “self” epitopes. This paradox dissolves somewhat once it is appreciated that, at any one time, a TCR will only have high functional sensitivity to a small subset of all its potential agonists, that is, when presented at low copy numbers, only this small subset will be able to activate the T cell. In this light, the self-nonself problem becomes a matter of keeping the TCR trained on the appropriate subset of salient epitopes. We review evidence and models that show how the co-receptors CD4 and CD8, as well as the “signal 2” costimulatory system, act to keep the TCR focussed on the appropriate agonist subset. On the theory of dynamic tuning of TCR specificity, both immune tolerance and specific reactivity against salient epitopes rely on continual regulation by other components of the immune system. We present a model of “avidity maturation” during the early phase of a T cell response.

Keywords

Functional Sensitivity Avidity Maturation Salient Epitope Costimulatory Receptor CD28 pMHC Molecule 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Mason D (1998) A very high level of crossreactivity is an essential feature of the T-cell receptor. Immunol Today 19:395–404PubMedCrossRefGoogle Scholar
  2. 2.
    Rudolph MG, Wilson IA (2002) The specificity of TCR/pMHC interaction. Curr Opin Immunol 14:52–65PubMedCrossRefGoogle Scholar
  3. 3.
    Hemmer B, Vergelli M, Pinilla C, Houghten R, Martin R (1998) Probing degeneracy in T-cell recognition using peptide combinatorial libraries. Immunol Today 19:163–168PubMedCrossRefGoogle Scholar
  4. 4.
    Wilson DB, Wilson DH, Schroder K, Pinilla C, Blondelle S, Houghten RA, Garcia KC (2004) Specificity and degeneracy of T cells. Mol Immunol 40:1047–1055PubMedCrossRefGoogle Scholar
  5. 5.
    Wooldridge L, Lissina A, van den Berg HA, Price DA, Sewell AK (2009) Tricks with tetramers: how to get the most from multimeric peptide-MHC. Immunology 126:147–164PubMedCrossRefGoogle Scholar
  6. 6.
    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 USA 93:4102–4107PubMedCrossRefGoogle Scholar
  7. 7.
    van den Berg HA, Rand DA, Burroughs NJ (2001) A reliable and safe T cell repertoire based on low-affinity T cell receptors. J Theor Biol 209:465–486CrossRefGoogle Scholar
  8. 8.
    van den Berg HA, Burroughs NJ, Rand DA (2002) Quantifying the strength of ligand antagonism in TCR triggering. Bull Math Biol 64:781–808CrossRefGoogle Scholar
  9. 9.
    van den Berg HA, Rand DA (2007) Quantitative theories of T-cell responsiveness. Immunol Rev 216:81–92PubMedGoogle Scholar
  10. 10.
    van den Berg HA, Rand DA (2004) Dynamics of T cell activation threshold tuning. J Theor Biol 228:397–416PubMedCrossRefGoogle Scholar
  11. 11.
    Stirk ER, Molina-París C, Berg HA van den(2008) Stochastic niche structure and diversity maintenance in the T cell repertoire. J Theor Biol 255:237–249Google Scholar
  12. 12.
    Gonzales PA, Carreño LJ, Coombs D, Mora JE, Palmeiri E, Goldstein B, Nathenson SG, Kalergis AM (2005) T cell receptor binding kinetics required for T cell activation depend on the density of the cognate ligand of the antigen-presenting cell. Proc Natl Acad Sci USA 102:4824–4829CrossRefGoogle Scholar
  13. 13.
    Iezzi G, Karjalainen K, Lanzavecchia A (1998) The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity 8:89–95PubMedCrossRefGoogle Scholar
  14. 14.
    Lanzavecchia A, Iezzi G, Viola A (1999) From TCR engagement to T cell activation: a kinetic view of T cell behavior. Cell 96:1–4PubMedCrossRefGoogle Scholar
  15. 15.
    Rachmilewitz J, Lanzavecchia A (2002) A temporal and spatial summation model for T cell activation: Signal integration and antigen decoding. Trends Immunol 23:592–595PubMedCrossRefGoogle Scholar
  16. 16.
    Bachmann MF, McKall-Faienza K, Schmits R, Bouchard D, Beach J, Speiser DE, Mak TW, Ohashi PS (1997) Distinct roles for LFA-1 and CD28 during activation of naive T cells: adhesion versus costimulation. Immunity 7:549–557PubMedCrossRefGoogle Scholar
  17. 17.
    Lanzavecchia A, Sallusto F (2000) Dynamics of T lymphocyte responses: intermediates, effectors, and memory cells. Science 290:92–97PubMedCrossRefGoogle Scholar
  18. 18.
    Sykulev Y, Joo M, Vturina I, Tsomides TJ, Eisen HN (1996) Evidence that a single peptide-MHC complex on a target cell can elicit a cytolytic T cell response. Immunity 4:565–571PubMedCrossRefGoogle Scholar
  19. 19.
    Wyer JR, Willcox BE, Gao GF, Gerth UC, Davis SJ, Bell JI, Merwe PA van der , Jakobsen BK (1999) T cell receptor and co-receptor CD8αα bind peptide-MHC independently and with distinct kinetics. Immunity 10:219–225PubMedCrossRefGoogle Scholar
  20. 20.
    Shores EW, Tran T, Grinberg A, Sommers CL, Shen H, Love PE (1997) Role of the multiple T cell receptor (TCR)-ζ chain signaling motifs in selection of the T cell repertoire. J Exp Med 185:893–900PubMedCrossRefGoogle Scholar
  21. 21.
    Werlen G, Palmer E (2002) The TCR signalosome: a dynamic structure with expanding complexity. Curr Opin Immunol 14:299–305PubMedCrossRefGoogle Scholar
  22. 22.
    Valitutti S, Lanzavecchia A (1997) Serial triggering of TCRs: a basis for the sensitivity and specificity of antigen recognition. Immunol Today 18:299–304PubMedCrossRefGoogle Scholar
  23. 23.
    Kalergis AM, Boucheron N, Doucey MA, Palmieri E, Goyarts EC, Vegh Z, Luesher IF, Nathenson SG (2001) Efficient T cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex. Nat Immunol 2:229–234PubMedCrossRefGoogle Scholar
  24. 24.
    McKeithan TW (1995) Kinetic proofreading in T-cell receptor signal transduction. Proc Natl Acad Sci USA 92:5042–5046PubMedCrossRefGoogle Scholar
  25. 25.
    Itoh Y, Germain RN (1997) Single cell analysis reveals regulated hierarchical T cell antigen receptor signaling thresholds and intraclonal heterogeneity for individual cytokine responses of CD4 +  cells. J Exp Med 186:757–766PubMedCrossRefGoogle Scholar
  26. 26.
    Rangel C, Angus J, Ghahramani Z, Lioumi M, Sotheran E, Gaiba A, Wild DL, Falciani F (2004) Modeling T-cell activation using gene expression profiling and state-space models. Bioinformatics 20:1361–1372PubMedCrossRefGoogle Scholar
  27. 27.
    Janeway Jr. CA (1992) The T cell receptor as a multicomponent signalling machine: CD4/CD8 coreceptors and CD45 in T cell activation. Annu Rev Immunol 10:645–674PubMedCrossRefGoogle Scholar
  28. 28.
    Luescher IF, Vivier E, Layer A, Mahiou J, Godeau F, Malissen B, Romero P (1995) CD8 modulation of T-cell antigen receptor-ligand interactions on living cytotoxic T lymphocytes. Nature 373:353–356PubMedCrossRefGoogle Scholar
  29. 29.
    Purbhoo MA, Boulter JM, Price DA, Vuidepot AL, Hourigan CS, Dunbar PR, Olson K, Dawson SJ, Phillips RE, Jakobsen BK, Bell JI, Sewell AK (2001) The human CD8 coreceptor effects cytotoxic T cell activation and antigen sensitivity primarily by mediating complete phosphorylation of the T cell receptor ζ chain. J Biol Chem 276:32786–32792PubMedCrossRefGoogle Scholar
  30. 30.
    Cawthon AG, Alexander-Miller MA (2002) Optimal colocalization of TCR and CD8 as a novel mechanism for the control of functional avidity. J Immunol 169:3492–3498PubMedGoogle Scholar
  31. 31.
    Pecht I, Gakamsky DM (2005) Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8 +  T-cells. FEBS Lett 579:3336–3341PubMedCrossRefGoogle Scholar
  32. 32.
    Wooldridge L, van den Berg HA, Glick M, Gostick E, Brenchley JM, Douek DC, Price DA, Sewell AK (2005) Interaction between the CD8 coreceptor and MHC class I stabilizes TCR-antigen complexes at the cell surface. J Biol Chem 280:27491–27501PubMedCrossRefGoogle Scholar
  33. 33.
    Holler PD, Kranz DM (2003) Quantitative analysis of the contribution of TCR/pepMHC affinity and CD8 to T cell activation. Immunity 18:255–264PubMedCrossRefGoogle Scholar
  34. 34.
    Arcaro A, Grégoire C, Bakker TR, Baldi L, Jordan M, Goffin L, Boucheron N, Wurm F, Merwe PA van der , Malissen B, Luescher IF (2001) CD8β endows CD8 with efficient coreceptor function by coupling T cell receptor/CD3 to raft-associated CD8/p56{ lck} complexes. J Exp Med 194:1485–1495PubMedCrossRefGoogle Scholar
  35. 35.
    Bosselut R, Zhang W, Ashe JM, Kopacz JL, Samuelson LE, Singer A (1999) Association of the adaptor molecule LAT with CD4 and CD8 coreceptors identifies a new coreceptor function in T cell receptor signal transduction. J Exp Med 190:1517–1525PubMedCrossRefGoogle Scholar
  36. 36.
    Brdičková N, Brdička T, Angelisová P, Horváth O, Špiča J, Hilgert I, Pačes J, Simeoni L, Kliche S, Merten C, Schraven B, Hořejší V (2003) LIME: a new membrane raft-associated adaptor protein involved in CD4 and CD8 coreceptor signaling. J Exp Med 198:1453–1462PubMedCrossRefGoogle Scholar
  37. 37.
    Berg HA van den , Wooldridge L, Laugel B, Sewell (2007) AK Coreceptor CD8-driven modulation of T cell antigen receptor specificity. J Theor Biol 249:395–408Google Scholar
  38. 38.
    Filipp D, Leung BL, Zhang J, Veillette A, Julius M (2004) Enrichment of lck in lipid rafts regulates colocalized fyn activation and the initiation of proximal signals through TCRαβ. J Immunol 172:4266–4274PubMedGoogle Scholar
  39. 39.
    Bosselut R, Kubo S, Guinter T, Kopacz JL, Altman JD, Feigenbaum L, Singer A (2000) Role of CD8β domains in CD8 coreceptor function: importance for MHC I binding, signaling, and positive selection of CD8 +  T cells in the Thymus. Immunity 12:409–418PubMedCrossRefGoogle Scholar
  40. 40.
    Gangadharan D, Cheroute H (2004) The CD8 isoform CD8αα is not a functional homologue of the TCR co-receptor CD8αβ. Curr Opin Immunol 16:264–270PubMedCrossRefGoogle Scholar
  41. 41.
    Arcaro A, Grégoire C, Boucheron N, Stolz S, Palmer E, Malissen B, Luescher IF (2000) Essential role of CD8 palmitoylation in CD8 coreceptor function. J Immunol 165:2068–2076PubMedGoogle Scholar
  42. 42.
    Doucey MA, Legler D, Boucheron N, Cerottini JC, Bron C, Luescher IF (2001) CTL activation is induced by cross-linking of TCR/MHC-peptide-CD8/p56{ lck} adducts in rafts. Eur J Immunol 31:1561–1570PubMedCrossRefGoogle Scholar
  43. 43.
    Hutchinson SL, Wooldridge L, Tafuro S, Laugel B, Glick M, Boulter JM, Jakobsen BK, Price DA, Sewell AK (2003) The CD8 T cell coreceptor exhibits disproportionate biological activity at extremely low binding affinities. J Biol Chem 278:24285–24293PubMedCrossRefGoogle Scholar
  44. 44.
    Wooldridge L, Lissina A, Vernazza J, Gostick E, Laugel B, Hutchinson SL, Mirza F, Dunbar PR, Boulter JM, Glick M, Cerundolo V, van den Berg HA, Price DA, Sewell AK (2007) Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class I invariant region. Eur J Immunol 37:1323–1333PubMedCrossRefGoogle Scholar
  45. 45.
    Maile R, Siler CA, Kerry SE, Midkiff KE, Collins EJ, Frelinger JA (2005) Peripheral “CD8 tuning” dynamically modulates the size and responsiveness of an antigen-specific T cell pool in vivo. J Immunol 174:619–627PubMedGoogle Scholar
  46. 46.
    Apte SH, Baz A, Groves P, Kelso A, Kienzle N (2008) Interferon-γ and interleukin-4 reciprocally regulate CD8 expression in CD8 +  T cells. Proc Natl Acad Sci USA 105:17475–17480PubMedCrossRefGoogle Scholar
  47. 47.
    Park JH, Adoro S, Lucas PJ, Sarafova SD, Alag AS, Doan LL, Erman B, Liu X, Ellmeier W, Bosselut R, Feigenbaum L, Singer A (2007) ‘Coreceptor tuning’: cytokine signals transcriptionally tailor CD8 coreceptor expression to the self-specificity of the TCR. Nat Immunol 8:1049–1058PubMedCrossRefGoogle Scholar
  48. 48.
    Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Holenbeck AE, Lerman MA, Naji A, Caton AJ (2001) Thymic selection of CD4 + CD25 +  regulatory T cells induced by an agonist self-peptide. Nat Immunol 2:301–306PubMedCrossRefGoogle Scholar
  49. 49.
    Mittrücker HW, Shahinian A, Bouchard D, Kündig TM, Mak TW (1996) Induction of unresponsiveness and impaired T cell expansion by staphylococcal enterotoxin B in CD28-deficient mice. J Exp Med 183:2481–2488PubMedCrossRefGoogle Scholar
  50. 50.
    Kündig TM, Shahinian A, Kawai K, Mittrücker HW, Sebzda E, Bachmann MF, Mak TW, Ohasi PS (1996) Duration of TCR stimulation determines costimulatory requirement of T cells. Immunity 5:41–52PubMedCrossRefGoogle Scholar
  51. 51.
    Greenwald RJ, Boussiotis VA, Lorsbach RB, Abbas AK, Sharpe AH (2001) CTLA-4 regulates induction of anergy in vivo. Immunity 14:145–155PubMedCrossRefGoogle Scholar
  52. 52.
    Roncarolo MG, Levings MK (2000) The role of different subsets of T regulatory cells in controlling autoimmunity. Curr Opin Immunol 12:676–683PubMedCrossRefGoogle Scholar
  53. 53.
    Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4 + CD25 +  immunoregulatory T cells that control autoimmune diabetes. Immunity 12:431–440PubMedCrossRefGoogle Scholar
  54. 54.
    Parham P (2000) The immune system. Garland Publishing, New YorkGoogle Scholar
  55. 55.
    Keller AM, Schildknecht A, Xiao Y, van den Broek M, Borst J (2008) Expression of costimulatory ligand CD70 on steady-state dendritic cells breaks CD8 +  T cell tolerance and permits effective immunity. Immunity 29:1–13CrossRefGoogle Scholar
  56. 56.
    Rudd CE, Schneider H (2003) Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat Rev Immunol 3:544–556PubMedCrossRefGoogle Scholar
  57. 57.
    Watts TH (2005) TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 23:23–68PubMedCrossRefGoogle Scholar
  58. 58.
    Krummel M, Allison JP (1995) CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 182:459–465PubMedCrossRefGoogle Scholar
  59. 59.
    Salomon B, Bluestone JA (2001) Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol 19:225–252PubMedCrossRefGoogle Scholar
  60. 60.
    Davis MM, Krogsgaard M, Huppa JB, Sumen C, Purbhoo MA, Irvine DJ, Wu LC, Ehrlich L (2003) Dynamics of cell surface molecules during T cell recognition. Annu Rev Biochem 72:717–742PubMedCrossRefGoogle Scholar
  61. 61.
    Collins AV, Brodie DW, Gilbert RJC, Iaboni A, Manso-Sancho R, Stuart DI, Merwe PA van der , Davis SJ (2002) The interaction properties of costimulatory molecules revisited. Immunity 17:201–210PubMedCrossRefGoogle Scholar
  62. 62.
    Egen JG, Kuhns MS, Allison JP (2002) CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol 3:611–618PubMedCrossRefGoogle Scholar
  63. 63.
    Egen JG, Allison JP (2002) Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 16:23–35PubMedCrossRefGoogle Scholar
  64. 64.
    Teh HS, Teh SJ (1997) High concentrations of antigenic ligand activate and do not tolerize naive T cells in the absence of CD28/B7 costimulation. Cell Immunol 179:74–83PubMedCrossRefGoogle Scholar
  65. 65.
    Stipdonk MJB van , Lemmens EE, Schoenberger SP (2001) Naïve CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation. Nat Immunol 2: 423–429PubMedGoogle Scholar
  66. 66.
    Sansom DM (2000) CD28, CTLA-4 and their ligands: who does what and to whom? Immunology 101:169–177PubMedCrossRefGoogle Scholar
  67. 67.
    Wells AD, Gudmundsdottir H, Turka LA (1997) Following the fate of individual T cells throughout activation and clonal expansion—signals from T cell receptor and CD28 differently regulate the induction and duration of a proliferative response. J Clin Invest 71:3173–3183CrossRefGoogle Scholar
  68. 68.
    Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB (2002) The CD28 signalling pathway regulates glucose metabolism. Immunity 16:769–777PubMedCrossRefGoogle Scholar
  69. 69.
    Bromley SK, Iaboni A, Davis SJ, Whitty A, Green JM, Shaw AS, Weiss A, Dustin ML (2001) The immunological synapse and CD28-CD80 interactions. Nat Immunol 2:1159–1166PubMedCrossRefGoogle Scholar
  70. 70.
    Truitt KE, Hicks CM, Imboden JB (1994) Stimulation of CD28 triggers an association between CD28 and phosphatidylinositol 3-kinase in Jurkat T cells. J Exp Med 179:1071–1076PubMedCrossRefGoogle Scholar
  71. 71.
    Marengére LEM, Okkenhaug K, Clavreul A, Couez D, Gibson S, Mills GB, Mak TW, Rottapel R (1997) The SH3 domain of Ikt/Emt binds to proline-rich sequences in the cytoplasmic domain of the T cell costimulatory receptor CD28. J Immunol 159:3220–3229PubMedGoogle Scholar
  72. 72.
    Viola A, Schroeder S, Sakakibara Y, Lanzavecchia A (1999) T lymphocyte costimulation mediated by reorganization of membrane microdomains. Science 283:680–682PubMedCrossRefGoogle Scholar
  73. 73.
    Wülfing C, Davis MM (1998) A receptor/cytoskeletal movement triggered by costimulation during T cell activation. Science 282:2266–2269PubMedCrossRefGoogle Scholar
  74. 74.
    Diehn M, Alizadeh AA, Rando OJ, Liu CL, Stankunas K, Botstein D, Crabtree GR, Brown PO (2002) Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation. Proc Natl Acad Sci USA 99:11796–11801PubMedCrossRefGoogle Scholar
  75. 75.
    Riley JL, Mao M, Kobayashi S, Biery M, Burchard J, Cavet G, Gregson BG, June CH, Linsey PS (2002) Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Proc Natl Acad Sci USA 99:11790–11795PubMedCrossRefGoogle Scholar
  76. 76.
    Walunas TL, Bakker CY, Bluestone JA (1996) CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med 183:2541–2550PubMedCrossRefGoogle Scholar
  77. 77.
    Gajewski TF, Fallarino F, Fields PE, Rivas F, Alegre ML (2001) Absence of CTLA-4 lowers the activation threshold of primed CD8 +  TCR-transgenic T cells: lack of correlation with src homology domain 2-containing protein phosphatase. J Immunol 166:3900–3907PubMedGoogle Scholar
  78. 78.
    Brunner MC, Chambers CA, Chan FKM, Hanke J, Winoto A, Allison JP (1999) CTLA-4-mediated inhibition of early events of T cell proliferation. J Immunol 162:5813–5820PubMedGoogle Scholar
  79. 79.
    Doyle AM, Mullen AC, Villarino AV, Hutchins AS, High FA, Lee HW, Thompson CB, Reiner SL (2001) Induction of cytotoxic T lymphocyte antigen 4(CTLA-4) restricts clonal expansion of helper T cells. J Exp Med 194:893–902PubMedCrossRefGoogle Scholar
  80. 80.
    Greenwald R, Oosterwegel M, Woude D van der , Kubal A, Mandelbrot DA, Boussiotis VA, Sharpe AH (2002) CTLA-4 regulates cell cycle progression during a primary immune response. Eur J Immunol 32:366–373PubMedCrossRefGoogle Scholar
  81. 81.
    Krummel M, Allison JP (1996) CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med 183:2533–2540PubMedCrossRefGoogle Scholar
  82. 82.
    Chikuma S, Imboden JB, Bluestone JA (2003) Negative regulation of T cell receptor-lipid raft interaction by cytotoxic T lymphocyte-associated antigen 4. J Exp Med 197:129–135PubMedCrossRefGoogle Scholar
  83. 83.
    Lee KM, Chuang E, Griffin M, Khattri R, Hong DK, Zhang W, Straus D, Samelson LE, Thompson CB, Bluestone JA (1998) Molecular basis of T cell inactivation by CTLA-4. Science 282:2263–2266PubMedCrossRefGoogle Scholar
  84. 84.
    Chuang E, Fisher TS, Morgan RW, Robbins MD, Duerr JM, Vander Heiden MG, Gardner JP, Hambor JE, Neveu MJ, Thompson CB (2000) The CD28 and CTLA-4 receptors associate with the serine/threonine phosphatase PP2A. Immunity 13:313–322PubMedCrossRefGoogle Scholar
  85. 85.
    Alegre ML, Noel PJ, Eisfelder BJ, Chuang E, Clark MR, Reiner SL, Thompson CB (1996) Regulation of surface and intracellular expression of CTLA-4 on mouse T cells. J Immunol 157:4762–4770PubMedGoogle Scholar
  86. 86.
    Kuhns MS, Epshteyn V, Sobel RA, Allison JP (2000) Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates the size, reactivity, and function of a primed pool of CD4 +  T cells. Proc Natl Acad Sci USA 97:12711–12716PubMedCrossRefGoogle Scholar
  87. 87.
    Schwartz JCD, Zhang X, Nathenson SG, Almo SC (2002) Structural mechanisms of costimulation. Nat Immunol 3:427–434PubMedCrossRefGoogle Scholar
  88. 88.
    Price DA, Brenchley JM, Ruff LE, Betts MR, Hill BJ, Roederer M, Koup RA, Migueles SA, Gostick E, Wooldridge L, Sewell AK, Connors M, Douek DC (2005) Avidity for antigen shapes clonal dominance in CD8 +  T cell populations specific for persistent DNA viruses. J Exp Med 202:1349–1361PubMedCrossRefGoogle Scholar
  89. 89.
    Berg HA van den , Rand DA (2004) Foreigness as a matter of degree: the relative immunogenicity of peptide/MHC ligands. J Theor Biol 231:535–548PubMedCrossRefGoogle Scholar
  90. 90.
    Sansom DM, Manzotti CN, Zheng Y (2003) What’s the difference between CD80 and CD86? Trends Immunol 24:313–318CrossRefGoogle Scholar
  91. 91.
    Guermonprez P, Valladeau J, Zitvogel L, Théry C, Amigorena S (2002) Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol 20:621–667PubMedCrossRefGoogle Scholar
  92. 92.
    Balkhi MY, Latchumanan VK, Singh B, Sharma P, Natarajan K (2004) Cross-regulation of CD86 by CD80 differentially regulates T helper responses from Mycobacterium tuberculosis secretory antigen-activated dendritic cell subsets. J Leukoc Biol 75:874–883PubMedCrossRefGoogle Scholar
  93. 93.
    Bousso P, Levraud JP, Kourilsky P, Abastado JP (1999) The composition of a primary T cell response is largely determined by the timing of recruitment of individual T cell clones. J Exp Med 189:1591–1600PubMedCrossRefGoogle Scholar
  94. 94.
    Sourdive DJ, Murali-Krishna K, Altman JD, Zajac AJ, Whitmire JK, Pannetier C, Kourilsky P, Evavold B, Sette A, Ahmed R (1998) Conserved T cell receptor repertoire in primary and memory CD8 T cell responses to an acute viral infection. J Exp Med 188:71–82PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Warwick Systems Biology CentreUniversity of WarwickCoventryUK

Personalised recommendations