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The Biophysics of T Lymphocyte Activation In Vitro and In Vivo

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Cell Communication in Nervous and Immune System

Part of the book series: Results and Problems in Cell Differentiation ((RESULTS,volume 43))

Abstract

T cell activation is crucial for the development of specific immune reactions. It requires physical contact between T cells and antigen-presenting cells (APC). Since these cells are initially located at distinct positions in the body, they have to migrate and find each other within secondary lymphoid organs. After encountering each other both cells have to maintain a close membrane contact sufficiently long to ensure successful signaling. Thus, there is the necessity to temporarily synchronize the motile behavior of these cells. Initially, it had been proposed that during antigen recognition, T cells receive a stop signal and maintain a stable contact with APC for several hours when an appropriate APC has been encountered. However, direct cell observation via time-lapse microscopy in vitro and in vivo has revealed a different picture. While long contacts can be observed, many interactions appear to be very short and sequential despite efficient signaling. Thus, two concepts addressing the biophysics of T cell activation have emerged. The single encounter model proposes that after a period of dynamic searching, a T cell stops to interact with one appropriately presenting APC until signaling is completed. The serial encounter model suggests that T cells are able to collect a series of short signals by different APC until a critical activation threshold is achieved. Future research needs to clarify the relative importance of short and dynamic versus long-lived T cell–APC encounters for the outcome of T cell activation. Furthermore, a thorough understanding of the molecular events underlying the observed complex motility patterns will make these phenomena amenable for intervention, which might result in the identification of new types of immune modulating drugs.

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References

  1. Alberola-Ila J et al. (1995) Selective requirement for MAP kinase activation in thymocyte differentiation. Nature 373(6515):620–623

    Article  PubMed  CAS  Google Scholar 

  2. Bajenoff M, Granjeaud S, Guerder S (2003) The strategy of T cell antigen-presenting cell encounter in antigen-draining lymph nodes revealed by imaging of initial T cell activation. J Exp Med 198(5):715–724

    Article  PubMed  CAS  Google Scholar 

  3. Bhakta NR, Oh DY, Lewis RS (2005) Calcium oscillations regulate thymocyte motility during positive selection in the three-dimensional thymic environment. Nat Immunol 6(2):143–151

    Article  PubMed  CAS  Google Scholar 

  4. Borovsky Z et al. (2002) Serial triggering of T cell receptors results in incremental accumulation of signaling intermediates. J Biol Chem 277(24):21529–21536

    Article  PubMed  CAS  Google Scholar 

  5. Bousso P et al. (2002) Dynamics of thymocyte–stromal cell interactions visualized by two-photon microscopy. Science 296(5574):1876–1880

    Article  PubMed  CAS  Google Scholar 

  6. Bradley LM, Watson SR (1996) Lymphocyte migration into tissue: the paradigm derived from CD4 subsets. Curr Opin Immunol 8(3):312–320

    Article  PubMed  CAS  Google Scholar 

  7. Brocker T (1997) Survival of mature CD4 T lymphocytes is dependent on major histocompatibility complex class-II expressing dendritic cells. J Exp Med 186(8):1223–1232

    Article  PubMed  CAS  Google Scholar 

  8. Butcher EC, Picker LJ (1996) Lymphocyte homing and homeostasis. Science 272(5258):60–66

    Article  PubMed  CAS  Google Scholar 

  9. Cella M et al. (1997) Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature 388(6644):782–787

    Article  PubMed  CAS  Google Scholar 

  10. Correia-Neves M et al. (2001) The shaping of the T cell repertoire. Immunity 14(1):21–32

    Article  PubMed  CAS  Google Scholar 

  11. Dustin ML, Chan AC (2000) Signaling takes shape in the immune system. Cell 103(2):283–294

    Article  PubMed  CAS  Google Scholar 

  12. Dustin ML, de Fougerolles AR (2001) Reprogramming T cells: the role of extracellular matrix in coordination of T cell activation and migration. Curr Opin Immunol 13(3):286–290

    Article  PubMed  CAS  Google Scholar 

  13. Dustin ML et al. (1997) Antigen receptor engagement delivers a stop signal to migrating T lymphocytes. Proc Natl Acad Sci USA 94(8):3909–3913

    Article  PubMed  CAS  Google Scholar 

  14. Dustin ML, Allen PM, Shaw AS (2001) Environmental control of immunological synapse formation and duration. Trends Immunol 22(4):192–194

    Article  PubMed  CAS  Google Scholar 

  15. Faroudi M et al. (2003) Cutting edge: T lymphocyte activation by repeated immunological synapse formation and intermittent signaling. J Immunol 171(3):1128–1132

    PubMed  CAS  Google Scholar 

  16. Fontenot JD et al. (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22(3):329–341

    Article  PubMed  CAS  Google Scholar 

  17. Forster R et al. (1999) CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99(1):23–33

    Article  PubMed  CAS  Google Scholar 

  18. Friedl P, Brocker EB (2002) TCR triggering on the move: diversity of T cell interactions with antigen-presenting cells. Immunol Rev 186:83–89

    Article  PubMed  CAS  Google Scholar 

  19. Friedl P, Gunzer M (2001) Interaction of T cells with APCs: the serial encounter model. Trends Immunol 22(4):187–191

    Article  PubMed  CAS  Google Scholar 

  20. Friedl P et al. (1994) Locomotor phenotypes of unstimulated CD45RAhigh and CD45ROhigh CD4+ and CD8+ lymphocytes in three-dimensional collagen lattices. Immunology 82(4):617–624

    PubMed  CAS  Google Scholar 

  21. Friedl P, Noble PB, Zanker KS (1995) T lymphocyte locomotion in a three-dimensional collagen matrix. Expression and function of cell adhesion molecules. J Immunol 154(10):4973–4985

    PubMed  CAS  Google Scholar 

  22. Friedl P et al. (1998) CD4+ T lymphocytes migrating in three-dimensional collagen lattices lack focal adhesions and utilize beta1 integrin-independent strategies for polarization, interaction with collagen fibers and locomotion. Eur J Immunol 28(8):2331–2343

    Article  PubMed  CAS  Google Scholar 

  23. Fuchs EJ, Matzinger P (1992) B cells turn off virgin but not memory T cells. Science 258(5085):1156–1159

    Article  PubMed  CAS  Google Scholar 

  24. Germain RN, Jenkins MK (2004) In vivo antigen presentation. Curr Opin Immunol 16(1):120–125

    Article  PubMed  CAS  Google Scholar 

  25. Goldrath AW, Bevan MJ (1999) Selecting and maintaining a diverse T cell repertoire. Nature 402(6759):255–262

    Article  PubMed  CAS  Google Scholar 

  26. Gretz JE, Anderson AO, Shaw S (1997) Cords, channels, corridors and conduits: critical architectural elements facilitating cell interactions in the lymph node cortex. Immunol Rev 156:11–24

    Article  PubMed  CAS  Google Scholar 

  27. Gretz JE et al. (2000) Lymph-borne chemokines and other low molecular weight molecules reach high endothelial venules via specialized conduits while a functional barrier limits access to the lymphocyte microenvironments in lymph node cortex. J Exp Med 192(10):1425–1440

    Article  PubMed  CAS  Google Scholar 

  28. Gunzer M et al. (2000) Antigen presentation in extracellular matrix: interactions of T cells with dendritic cells are dynamic, short lived, and sequential. Immunity 13(3):323–332

    Article  PubMed  CAS  Google Scholar 

  29. Gunzer M et al. (2004) A spectrum of biophysical interaction modes between T cells and different antigen-presenting cells during priming in 3D collagen and in vivo. Blood 104(9):2801–2809

    Article  PubMed  CAS  Google Scholar 

  30. Gunzer M et al. (2005) Systemic administration of a TLR7 ligand leads to transient immune incompetence due to peripheral-blood leukocyte depletion. Blood 106(7):2424–2432

    Article  PubMed  CAS  Google Scholar 

  31. Hugues S et al. (2004) Distinct T cell dynamics in lymph nodes during the induction of tolerance and immunity. Nat Immunol 5(12):1235–1242

    Article  PubMed  CAS  Google Scholar 

  32. Hurez V et al. (2003) Restricted clonal expression of IL-2 by naive T cells reflects differential dynamic interactions with dendritic cells. J Exp Med 198(1):123–132

    Article  PubMed  CAS  Google Scholar 

  33. Hwang JM et al. (2004) A critical temporal window for selectin-dependent CD4+ lymphocyte homing and initiation of late-phase inflammation in contact sensitivity. J Exp Med 199(9):1223–1234

    Article  PubMed  CAS  Google Scholar 

  34. Iezzi G, Karjalainen K, Lanzavecchia A (1998) The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity 8(1):89–95

    Article  PubMed  CAS  Google Scholar 

  35. Irvine DJ, Purbhoo MA, Krogsgaard M, Davis MM (2002) Direct observation of ligand recognition by T cells. Nature 419(6909):845–849

    Article  PubMed  CAS  Google Scholar 

  36. Itano AA et al. (2003) Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity. Immunity 19(1):47–57

    Article  PubMed  CAS  Google Scholar 

  37. Jonuleit H et al. (2001) Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med 193(11):1285–1294

    Article  PubMed  CAS  Google Scholar 

  38. Kaldjian EP et al. (2001) Spatial and molecular organization of lymph node T cell cortex: a labyrinthine cavity bounded by an epithelium-like monolayer of fibroblastic reticular cells anchored to basement membrane-like extracellular matrix. Int Immunol 13(10):1243–1253

    Article  PubMed  CAS  Google Scholar 

  39. Kannagi R (2002) Regulatory roles of carbohydrate ligands for selectins in the homing of lymphocytes. Curr Opin Struct Biol 12(5):599–608

    Article  PubMed  CAS  Google Scholar 

  40. Kedl RM et al. (2000) T cells compete for access to antigen-bearing antigen-presenting cells. J Exp Med 192(8):1105–1113

    Article  PubMed  CAS  Google Scholar 

  41. Kupfer A, Singer SJ (1989) The specific interaction of helper T cells and antigen-presenting B cells. IV. Membrane and cytoskeletal reorganizations in the bound T cell as a function of antigen dose. J Exp Med 170(5):1697–1713

    Article  PubMed  CAS  Google Scholar 

  42. Lanzavecchia A, Sallusto F (2001) Antigen decoding by T lymphocytes: from synapses to fate determination. Nat Immunol 2(6):487–492

    Article  PubMed  CAS  Google Scholar 

  43. Lanzavecchia A, Lezzi G, Viola A (1999) From TCR engagement to T cell activation: a kinetic view of T cell behavior. Cell 96(1):1–4

    Article  PubMed  CAS  Google Scholar 

  44. Lee KH et al. (2002) T cell receptor signaling precedes immunological synapse formation. Science 295(5559):1539–1542

    Article  PubMed  CAS  Google Scholar 

  45. Lee KH et al. (2003) The immunological synapse balances T cell receptor signaling and degradation. Science 302(5648):1218–1222

    Article  PubMed  CAS  Google Scholar 

  46. Lindquist RL et al. (2004) Visualizing dendritic cell networks in vivo. Nat Immunol 5(12):1243–1250

    Article  PubMed  CAS  Google Scholar 

  47. Lukas M et al. (1996) Human cutaneous dendritic cells migrate through dermal lymphatic vessels in a skin organ culture model. J Invest Dermatol 106(6):1293–1299

    Article  PubMed  CAS  Google Scholar 

  48. Mackay CR (1993) Homing of naive, memory and effector lymphocytes. Curr Opin Immunol 5(3):423–427

    Article  PubMed  CAS  Google Scholar 

  49. Mehling A et al. (2001) Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation and systemic autoimmunity. J Exp Med 194(5):615–628

    Article  PubMed  CAS  Google Scholar 

  50. Mellman I, Steinman RM (2001) qDendritic cells: specialized and regulated antigen processing machines. Cell 106(3):255–258

    Article  PubMed  CAS  Google Scholar 

  51. Mempel TR, Henrickson SE, Von Andrian UH (2004) T cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427(6970):154–159

    Article  PubMed  CAS  Google Scholar 

  52. Miller MJ et al. (2002) Two-photon imaging of lymphocyte motility and antigen response in intact lymph node. Science 296(5574):1869–1873

    Article  PubMed  CAS  Google Scholar 

  53. Miller MJ et al. (2003) Autonomous T cell trafficking examined in vivo with intravital two-photon microscopy. Proc Natl Acad Sci USA 100(5):2604–2609

    Article  PubMed  CAS  Google Scholar 

  54. Miller MJ et al. (2004a) T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell motility in the lymph node. Proc Natl Acad Sci USA 101(4):998–1003

    Article  PubMed  CAS  Google Scholar 

  55. Miller MJ et al. (2004b) Imaging the single cell dynamics of CD4+ T cell activation by dendritic cells in lymph nodes. J Exp Med 200(7):847–856

    Article  PubMed  CAS  Google Scholar 

  56. Monks CR et al. (1998) Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395(6697):82–86

    Article  PubMed  CAS  Google Scholar 

  57. Moser B, Loetscher P (2001) Lymphocyte traffic control by chemokines. Nat Immunol 2(2):123–128

    Article  PubMed  CAS  Google Scholar 

  58. Negulescu PA et al. (1996) Polarity of T cell shape, motility, and sensitivity to antigen. Immunity 4(5):421–430

    Article  PubMed  CAS  Google Scholar 

  59. Nikolich-Zugich J, Slifka MK, Messaoudi I (2004) The many important facets of T-cell repertoire diversity. Nat Rev Immunol 4(2):123–132

    Article  PubMed  CAS  Google Scholar 

  60. Okada T et al. (2005) Antigen-engaged B cells undergo chemotaxis toward the T zone, form motile conjugates with helper T cells. PLoS Biol 3(6):e150

    Google Scholar 

  61. O'Neill EJ et al. (2004) Natural and induced regulatory T cells. Ann NY Acad Sci 1029(1):180–192

    Article  PubMed  CAS  Google Scholar 

  62. Palmer E (2003) Negative selection—clearing out the bad apples from the T cell repertoire. Nat Rev Immunol 3(5):383–391

    Article  PubMed  CAS  Google Scholar 

  63. Potsch C, Vohringer D, Pircher H (1999) Distinct migration patterns of naive and effector CD8 T cells in the spleen: correlation with CCR7 receptor expression and chemokine reactivity. Eur J Immunol 29(11):3562–3570

    Article  PubMed  CAS  Google Scholar 

  64. Probst HC et al. (2003) Inducible transgenic mice reveal resting dendritic cells as potent inducers of CD8+ T cell tolerance. Immunity 18(5):713–720

    Article  PubMed  CAS  Google Scholar 

  65. Rachmilewitz J, Lanzavecchia A (2002) A temporal and spatial summation model for T cell activation: signal integration and antigen decoding. Trends Immunol 23(12):592–595

    Article  PubMed  CAS  Google Scholar 

  66. Reif K et al. (2002) Balanced responsiveness to chemoattractants from adjacent zones determines B cell position. Nature 416:94–99

    Article  PubMed  Google Scholar 

  67. Richie LI et al. (2002) Imaging synapse formation during thymocyte selection: inability of CD3zeta to form a stable central accumulation during negative selection. Immunity 16(4):595–606

    Article  PubMed  CAS  Google Scholar 

  68. Rodriguez-Pinto D, Moreno JB (2005) B cells can prime naive CD4+ T cells in vivo in the absence of other professional antigen-presenting cells in a CD154-CD40-dependent manner. Eur J Immunol 35(4):1097–1105

    Article  PubMed  CAS  Google Scholar 

  69. Romani N et al. (2001) Migration of dendritic cells into lymphatics—the Langerhans cell example: routes, regulation, and relevance. Int Rev Cytol 207:237–270

    Article  PubMed  CAS  Google Scholar 

  70. Rosette C et al. (2001) The impact of duration versus extent of TCR occupancy on T cell activation: a revision of the kinetic proofreading model. Immunity 15(1):59–70

    Article  PubMed  CAS  Google Scholar 

  71. Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6(4):345–352

    Article  PubMed  CAS  Google Scholar 

  72. Sallusto F et al. (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401(6754):708–712

    Article  PubMed  CAS  Google Scholar 

  73. Sallusto F, Geginat J, Lanzavecchia A (2004) Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol 22(1):745–763

    Article  PubMed  CAS  Google Scholar 

  74. Sebzda E et al. (1999) Selection of the T cell repertoire. Annu Rev Immunol 17(1):829–874

    Article  PubMed  CAS  Google Scholar 

  75. Seder RA, Ahmed R (2003) Similarities and differences in CD4+ and CD8+ effector and memory T cell generation. Nat Immunol 4(9):835–842

    Article  PubMed  CAS  Google Scholar 

  76. Shakhar G et al. (2005) Stable T cell–dendritic cell interactions precede the development of both tolerance and immunity in vivo. Nat Immunol 6(7):707–714

    Article  PubMed  CAS  Google Scholar 

  77. Springer TA (1990) Adhesion receptors of the immune system. Nature 346(6283):425–434

    Article  PubMed  CAS  Google Scholar 

  78. Springer TA (1994) Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76(2):301–314

    Article  PubMed  CAS  Google Scholar 

  79. Stoll S, Delon J, Brotz TM, Germain RN (2002) Dynamic imaging of T cell–dendritic cell interactions in lymph nodes. Science 296(5574):1873–1876

    Article  PubMed  Google Scholar 

  80. Underhill DM et al. (1999) Dynamic interactions of macrophages with T cells during antigen presentation. J Exp Med 190(12):1909–1914

    Article  PubMed  CAS  Google Scholar 

  81. Ushiki T, Ohtani O, Abe K (1995) Scanning electron microscopic studies of reticular framework in the rat mesenteric lymph node. Anat Rec 241(1):113–122

    Article  PubMed  CAS  Google Scholar 

  82. Valitutti S et al. (1995) Sustained signaling leading to T cell activation results from prolonged T cell receptor occupancy. Role of T cell actin cytoskeleton. J Exp Med 181:577–584

    Article  PubMed  CAS  Google Scholar 

  83. Wei SH et al. (2003) A stochastic view of lymphocyte motility and trafficking within the lymph node. Immunol Rev 195:136–159

    Article  PubMed  CAS  Google Scholar 

  84. Westermann J et al. (2005) Naive, effector, and memory T lymphocytes efficiently scan dendritic cells in vivo: contact frequency in T cell zones of secondary lymphoid organs does not depend on LFA-1 expression and facilitates survival of effector T cells. J Immunol 174(5):2517-2524

    PubMed  CAS  Google Scholar 

  85. Witt CM et al. (2005) Directed migration of positively selected thymocytes visualized in real time. PLoS Biol 3(6):e160

    Google Scholar 

  86. Yasutomo K et al. (2000) The duration of antigen receptor signalling determines CD4+ versus CD8+ T-cell lineage fate. Nature 404(6777):506–510

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Matthias Gunzer .

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Eckart D. Gundelfinger Constanze I. Seidenbecher Burkhart Schraven

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Reichardt, P., Gunzer, M. (2006). The Biophysics of T Lymphocyte Activation In Vitro and In Vivo. In: Gundelfinger, E.D., Seidenbecher, C.I., Schraven, B. (eds) Cell Communication in Nervous and Immune System. Results and Problems in Cell Differentiation, vol 43. Springer, Berlin, Heidelberg . https://doi.org/10.1007/400_021

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