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  • Review Article
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T-cell activation by dendritic cells in the lymph node: lessons from the movies

Nature Reviews Immunology volume 8, pages 675–684 (2008)Cite this article

Key Points

  • Cellular interactions between T cells and dendritic cells (DCs) in lymph nodes are crucial for the initiation of adaptive cell-mediated immunity. Two-photon imaging offers the opportunity to track T-cell–DCs contacts in real-time and in vivo, providing insights into some of the most dynamic aspects of T-cell activation.

  • Within lymph nodes, T cells can receive signals during both short-lived and long-lived interactions with antigen-bearing DCs. These contacts are highly regulated events that are influenced by the timing of activation, signal strength, the inflammatory environment and the presence of other responding T cells.

  • The fate of individual T cells is influenced by the sequence of contacts with antigen-bearing DCs and their ability to integrate signals that are delivered during these interactions. Most often, optimal T-cell priming in vivo requires the formation of long-lived interactions with DCs.

  • Dynamic imaging of T-cell–DC interactions has also offered novel insights into fundamental mechanisms such as CD4+ T-cell help, intraclonal T-cell competition and suppression by regulatory T cells.

  • Two-photon studies that use model antigens have provided the conceptual framework which future studies will apply to clarify how T cells are activated by DCs during infections, and to explore how pathogens might modulate T-cell–DC contact dynamics.

Abstract

Interactions between T cells and dendritic cells (DCs) in the lymph nodes are crucial for initiating cell-mediated adaptive immune responses. With the help of two-photon imaging, the complexity of these cellular contacts in vivo has recently been captured in time-lapse movies in several immunological contexts. Well beyond the satisfaction of seeing a T-cell response as it happens, these experiments provide fundamental insights into the regulation and the biological meaning of T-cell–DC contact dynamics. This Review focuses on how this emerging field is changing our perception of T-cell activation by DCs.

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Figure 1: Intravital two-photon imaging of T-cell–DC interactions.
Figure 2: Sequences of T-cell–DC interactions during the course of an immune response.
Figure 3: Models for the gradual accumulation of stable T-cell–DC interactions over time.
Figure 4: T cells can interact with antigen-bearing DCs in lymph nodes in multiple ways.

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References

  1. von Andrian, U. H. & Mempel, T. R. Homing and cellular traffic in lymph nodes. Nature Rev. Immunol. 3, 867–878 (2003).

    Article  CAS  Google Scholar 

  2. Bousso, P., Bhakta, N. R., Lewis, R.B. & Robey, E. Dynamics of thymocyte–stromal cell interactions visualized by two- photon microscopy. Science 296, 1876–1880 (2002).

    Article  CAS  Google Scholar 

  3. Miller, M. J., Wei, S. H., Parker, I. & Cahalan, M. D. Two-photon imaging of lymphocyte motility and antigen response in intact lymph node. Science 296, 1869–1873 (2002). References 2 and 3 report the first application of two-photon imaging for the study of T-cell activation in lymphoid organs.

    Article  CAS  Google Scholar 

  4. Denk, W., Strickler, J. H. & Webb, W. W. Two-photon laser scanning fluorescence microscopy. Science 248, 73–76 (1990).

    Article  CAS  Google Scholar 

  5. Cahalan, M. D., Parker, I., Wei, S. H. & Miller, M. J. Two-photon tissue imaging: seeing the immune system in a fresh light. Nature Rev. Immunol. 2, 872–880 (2002).

    Article  CAS  Google Scholar 

  6. Germain, R. N., Miller, M. J., Dustin, M. L. & Nussenzweig, M. C. Dynamic imaging of the immune system: progress, pitfalls and promise. Nature Rev. Immunol. 6, 497–507 (2006).

    Article  CAS  Google Scholar 

  7. Beltman, J. B., Maree, A. F. & de Boer, R. J. Spatial modelling of brief and long interactions between T cells and dendritic cells. Immunol. Cell Biol. 85, 306–314 (2007).

    Article  CAS  Google Scholar 

  8. Beltman, J. B., Maree, A. F., Lynch, J. N., Miller, M. J. & de Boer, R. J. Lymph node topology dictates T cell migration behavior. J. Exp. Med. 204, 771–780 (2007).

    Article  CAS  Google Scholar 

  9. Bajenoff, M. et al. Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity 25, 989–1001 (2006).

    Article  CAS  Google Scholar 

  10. Marzo, A. L. et al. Initial T cell frequency dictates memory CD8+ T cell lineage commitment. Nature Immunol. 6, 793–799 (2005).

    Article  CAS  Google Scholar 

  11. Badovinac, V. P., Haring, J. S. & Harty, J. T. Initial T cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8+ T cell response to infection. Immunity 26, 827–841 (2007).

    Article  CAS  Google Scholar 

  12. Garcia, Z. et al. Competition for antigen determines the stability of T cell–dendritic cell interactions during clonal expansion. Proc. Natl Acad. Sci. USA 104, 4553–4558 (2007).

    Article  CAS  Google Scholar 

  13. Cavanagh, L. L. & Weninger, W. Dendritic cell behaviour in vivo: lessons learned from intravital two-photon microscopy. Immunol. Cell Biol. 86, 428–438 (2008).

    Article  CAS  Google Scholar 

  14. Stoll, S., Delon, J., Brotz, T. M. & Germain, R. N. Dynamic imaging of T cell-dendritic cell interactions in lymph nodes. Science 296, 1873–1876 (2002).

    Article  Google Scholar 

  15. Bousso, P. & Robey, E. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes. Nature Immunol. 4, 579–585 (2003). This study reports the rate of T-cell–DC encounters in the absence of antigen and establishes the occurrence of long-lived T-cell–DC interactions during CD8+ T-cell priming.

    Article  CAS  Google Scholar 

  16. Castellino, F. et al. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell–dendritic cell interaction. Nature 440, 890–895 (2006). This study shows that chemokines that are produced during CD4+ T-cell–DC interactions attract CCR5-expressing CD8+ T cells, which favour the occurrence of three-cell clusters.

    Google Scholar 

  17. Beuneu, H., Garcia, Z. & Bousso, P. Cutting edge: cognate CD4 help promotes recruitment of antigen-specific CD8 T cells around dendritic cells. J. Immunol. 177, 1406–1410 (2006).

    Article  CAS  Google Scholar 

  18. Lindquist, R. L. et al. Visualizing dendritic cell networks in vivo. Nature Immunol. 5, 1243–1250 (2004).

    Article  CAS  Google Scholar 

  19. Hugues, S. et al. Distinct T cell dynamics in lymph nodes during the induction of tolerance and immunity. Nature Immunol. 5, 1235–1242 (2004).

    Article  CAS  Google Scholar 

  20. Shakhar, G. et al. Stable T cell–dendritic cell interactions precede the development of both tolerance and immunity in vivo. Nature Immunol. 6, 707–714 (2005). References 19 and 20 compare T-cell–DC contact dynamics during an immunization regimen that induces either tolerance or priming.

    Article  CAS  Google Scholar 

  21. Miller, M. J., Hejazi, A. S., Wei, S. H., Cahalan, M. D. & Parker, I. 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, 998–1003 (2004).

    Article  CAS  Google Scholar 

  22. Odoardi, F. et al. Instant effect of soluble antigen on effector T cells in peripheral immune organs during immunotherapy of autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 104, 920–925 (2007).

    Article  CAS  Google Scholar 

  23. Tang, Q. et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nature Immunol. 7, 83–92 (2006).

    Article  CAS  Google Scholar 

  24. Hickman, H. D. et al. Direct priming of antiviral CD8+ T cells in the peripheral interfollicular region of lymph nodes. Nature Immunol. 9, 155–165 (2008).

    Article  CAS  Google Scholar 

  25. Donnadieu, E., Bismuth, G. & Trautmann, A. Antigen recognition by helper T cells elicits a sequence of distinct changes of their shape and intracellular calcium. Curr. Biol. 4, 584–595 (1994).

    Article  CAS  Google Scholar 

  26. Negulescu, P. A., Krasieva, T. B., Khan, A., Kerschbaum, H. H. & Cahalan, M. D. Polarity of T cell shape, motility, and sensitivity to antigen. Immunity 4, 421–430 (1996).

    Article  CAS  Google Scholar 

  27. Dustin, M. L., Bromley, S. K., Kan, Z., Peterson, D. A. & Unanue, E. R. Antigen receptor engagement delivers a stop signal to migrating T lymphocytes. Proc. Natl Acad. Sci. USA 94, 3909–3913 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Wei, S. H. et al. Ca2+ signals in CD4+ T cells during early contacts with antigen-bearing dendritic cells in lymph node. J. Immunol. 179, 1586–1594 (2007).

    Article  CAS  Google Scholar 

  30. Asperti-Boursin, F., Real, E., Bismuth, G., Trautmann, A. & Donnadieu, E. CCR7 ligands control basal T cell motility within lymph node slices in a phosphoinositide 3-kinase-independent manner. J. Exp. Med. 204, 1167–1179 (2007).

    Article  CAS  Google Scholar 

  31. Fischer, U. B. et al. MHC class II deprivation impairs CD4 T cell motility and responsiveness to antigen-bearing dendritic cells in vivo. Proc. Natl Acad. Sci. USA 104, 7181–7186 (2007).

    Article  CAS  Google Scholar 

  32. Hugues, S. et al. Dynamic imaging of chemokine-dependent CD8+T cell help for CD8+T cell responses. Nature Immunol. 8, 921–930 (2007).

    Article  CAS  Google Scholar 

  33. Friedman, R. S., Jacobelli, J. & Krummel, M. F. Surface-bound chemokines capture and prime T cells for synapse formation. Nature Immunol. 7, 1101–1108 (2006).

    Article  CAS  Google Scholar 

  34. Miller, M. J., Safrina, O., Parker, I. & Cahalan, M. D. Imaging the single cell dynamics of CD4+ T cell activation by dendritic cells in lymph nodes. J. Exp. Med. 200, 847–856 (2004).

    Article  CAS  Google Scholar 

  35. Mempel, T. R., Henrickson, S. E. & Von Andrian, U. H. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427, 154–159 (2004). This study reports that CD8+ T cells undergo a phase of transient interactions with DCs during the first hours of the activation process, prior to establishing long-lived contacts.

    Article  CAS  Google Scholar 

  36. Hugues, S., Boissonnas, A., Amigorena, S. & Fetler, L. The dynamics of dendritic cell–T cell interactions in priming and tolerance. Curr. Opin. Immunol. 18, 491–495 (2006).

    Article  CAS  Google Scholar 

  37. Skokos, D. et al. Peptide–MHC potency governs dynamic interactions between T cells and dendritic cells in lymph nodes. Nature Immunol. 8, 835–844 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  39. Huppa, J. B., Gleimer, M., Sumen, C. & Davis, M. M. Continuous T cell receptor signaling required for synapse maintenance and full effector potential. Nature Immunol. 4, 749–755 (2003).

    Article  CAS  Google Scholar 

  40. Costello, P. S., Gallagher, M. & Cantrell, D. A. Sustained and dynamic inositol lipid metabolism inside and outside the immunological synapse. Nature Immunol. 3, 1082–1089 (2002).

    Article  CAS  Google Scholar 

  41. Fabre, S. et al. Stable activation of phosphatidylinositol 3-kinase in the T cell immunological synapse stimulates Akt signaling to FoxO1 nuclear exclusion and cell growth control. J. Immunol. 174, 4161–4171 (2005).

    Article  CAS  Google Scholar 

  42. Harriague, J. & Bismuth, G. Imaging antigen-induced PI3K activation in T cells. Nature Immunol. 3, 1090–1096 (2002).

    Article  CAS  Google Scholar 

  43. Schrum, A. G. & Turka, L. A. The proliferative capacity of individual naive CD4+ T cells is amplified by prolonged T cell antigen receptor triggering. J. Exp. Med. 196, 793–803 (2002).

    Article  CAS  Google Scholar 

  44. Curtsinger, J. M., Johnson, C. M. & Mescher, M. F. CD8 T cell clonal expansion and development of effector function require prolonged exposure to antigen, costimulation, and signal 3 cytokine. J. Immunol. 171, 5165–5171 (2003).

    Article  CAS  Google Scholar 

  45. Celli, S., Lemaitre, F. & Bousso, P. Real-time manipulation of T cell-dendritic cell interactions in vivo reveals the importance of prolonged contacts for CD4+ T cell activation. Immunity 27, 625–634 (2007). This study describes an approach to control the duration of T-cell–DC contacts in vivo and uses it to demonstrate the functional importance of long-lived interactions.

    Article  CAS  Google Scholar 

  46. Dustin, M. L. T-cell activation through immunological synapses and kinapses. Immunol. Rev. 221, 77–89 (2008).

    Article  CAS  Google Scholar 

  47. Yeh, J. H., Sidhu, S. S. & Chan, A. C. Regulation of a late phase of T cell polarity and effector functions by Crtam. Cell 132, 846–859 (2008).

    Article  CAS  Google Scholar 

  48. Henrickson, S. E. et al. T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation. Nature Immunol. 9, 282–291 (2008). This study carefully examines the parameters that influence the duration of the initial phase of transient T-cell–DC contacts during activation.

    Article  CAS  Google Scholar 

  49. Scholer, A., Hugues, S., Boissonnas, A., Fetler, L. & Amigorena, S. Intercellular adhesion molecule-1-dependent stable interactions between T cells and dendritic cells determine CD8+ T cell memory. Immunity 28, 258–270 (2008).

    Article  CAS  Google Scholar 

  50. Schneider, H. et al. Reversal of the TCR stop signal by CTLA-4. Science 313, 1972–1975 (2006).

    Article  CAS  Google Scholar 

  51. Sims, T. N. et al. Opposing effects of PKCq and WASp on symmetry breaking and relocation of the immunological synapse. Cell 129, 773–785 (2007).

    Article  CAS  Google Scholar 

  52. Bhakta, N. R., Oh, D. Y. & Lewis, R. S. Calcium oscillations regulate thymocyte motility during positive selection in the three-dimensional thymic environment. Nature Immunol. 6, 143–151 (2005).

    Article  CAS  Google Scholar 

  53. Tadokoro, C. E. et al. Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J. Exp. Med. 203, 505–511 (2006).

    Article  CAS  Google Scholar 

  54. Zinselmeyer, B. H. et al. In situ characterization of CD4+ T cell behavior in mucosal and systemic lymphoid tissues during the induction of oral priming and tolerance. J. Exp. Med. 201, 1815–1823 (2005).

    Article  CAS  Google Scholar 

  55. Celli, S., Garcia, Z. & Bousso, P. CD4 T cells integrate signals delivered during successive DC encounters in vivo. J. Exp. Med. 202, 1271–1278 (2005).

    Article  CAS  Google Scholar 

  56. Woodland, D. L. & Dutton, R. W. Heterogeneity of CD4+ and CD8+ T cells. Curr. Opin. Immunol. 15, 336–342 (2003).

    Article  CAS  Google Scholar 

  57. Kaech, S. M. & Wherry, E. J. Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection. Immunity 27, 393–405 (2007).

    Article  CAS  Google Scholar 

  58. Stemberger, C. et al. A single naive CD8+ T cell precursor can develop into diverse effector and memory subsets. Immunity 27, 985–997 (2007).

    Article  CAS  Google Scholar 

  59. Chang, J. T. et al. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315, 1687–1691 (2007).

    Article  CAS  Google Scholar 

  60. Millington, O. R. et al. Malaria impairs T cell clustering and immune priming despite normal signal 1 from dendritic cells. PLoS Pathog. 3, 1380–1387 (2007).

    Article  CAS  Google Scholar 

  61. Huang, J. H. et al. Requirements for T lymphocyte migration in explanted lymph nodes. J. Immunol. 178, 7747–7755 (2007).

    Article  CAS  Google Scholar 

  62. Miller, M. J., Wei, S. H., Cahalan, M. D. & Parker, I. Autonomous T cell trafficking examined in vivo with intravital two-photon microscopy. Proc. Natl Acad. Sci. USA 100, 2604–2609 (2003).

    Article  CAS  Google Scholar 

  63. Celli, S. & Bousso, P. Intravital two-photon imaging of T-cell priming and tolerance in the lymph node. Methods Mol. Biol. 380, 355–363 (2007).

    Article  Google Scholar 

  64. Worbs, T., Mempel, T. R., Bolter, J., von Andrian, U. H. & Forster, R. CCR7 ligands stimulate the intranodal motility of T lymphocytes in vivo. J. Exp. Med. 204, 489–495 (2007).

    Article  CAS  Google Scholar 

  65. Catron, D. M., Rusch, L. K., Hataye, J., Itano, A. A. & Jenkins, M. K. CD4+ T cells that enter the draining lymph nodes after antigen injection participate in the primary response and become central-memory cells. J. Exp. Med. 203, 1045–1054 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

I thank E. Robey and members of my laboratory for helpful discussions. The work of my laboratory is supported by the Institut Pasteur, Inserm and a Marie Curie Excellence grant.

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  1. G5 Dynamiques des Réponses Immunes, Equipe Avenir, Inserm U668, Institut Pasteur, 25 rue du Dr Roux 75724 Paris Cedex 15, France

    Philippe Bousso

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Supplementary information

Supplementary information S1 (movie)

Intravital imaging of T-cell–DC interactions in lymph nodes. Antigen-specificCD4+ T cells (red) and peptide-pulsed dendritic cells (DCs) (green) were imaged in the popliteal lymph node of an anesthetized mouse using two-photon laser scanning microscopy. Imaging was carried out at 33 hours, during the late phase of activation. (MOV 2791 kb)

Supplementary information S2 (movie)

T cells establish short interactions with DCs in the absence of antigen. This movie shows the behaviour of CD8+ T cells (red) and dendritic cells (DCs) (green) in the absence of antigen. Left panel: DCs are visualized in mice in which the yellow fluorescent protein molecule is expressed under the control of the CD11c promoter. Right panel: fluorescently labelled DCs were injected in the footpad and visualized in the lymph node 24 hours later. Scale bar = 10 mm. (MOV 924 kb)

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FURTHER INFORMATION

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Glossary

Lymph nodes

Secondary lymphoid organs that collect cells from the blood and the afferent lymph, and antigens from the lymph for presentation to T and B cells. The human body contains several hundred lymph nodes.

Two-photon laser scanning microscopy

(TPLSM). Laser-scanning microscopy that uses pulsed infrared laser light for the excitation of conventional fluorophores or fluorescent proteins. This technique greatly reduces photodamage of living specimens and improves depth of tissue penetration, owing to the low level of light scattering within the tissue.

Phototoxicity

The phenomenon by which illumination of fluorescent molecules in a cell causes damage and eventually cell death, most likely owing to the formation of oxygen radicals.

Intraclonal T-cell competition

The process during which numerous T cells face a limiting resource (such as antigen or cytokines) that results in a diminished T-cell activation efficiency on a per cell basis.

DEC-205

A membrane glycoprotein expressed by CD8+ DCs that acts as an endocytic receptor. Genetic or chemical coupling of antigenic fragments to a DEC-205-specific antibody permits efficient delivery of the conjugate to a large proportion of DCs in lymphoid tissues.

Immunolgical synapse

The specialized contact area that is formed between a T cell that is interacting with an antigen-presenting cell (APC); it consists of molecules required for adhesion and signalling. This structure is important for establishing T-cell adhesion and polarity, is influenced by the cytoskeleton and transduces highly controlled secretory signals, thereby allowing the directed release of cytokines or lytic granules towards the APC or target cell.

L-selectin

A cell adhesion molecule that is expressed at the surface of most circulating lymphocytes, including naive T cells. It permits lymphocyte homing to the lymph node through high endothelial venules.

Wiskott–Aldrich syndrome protein

(WASP). WASP is an actin regulator that is involved in the formation of the immunological synapse. Mutations in WASP cause a life-threatening X-linked immunodeficiency that is characterized by thrombocytopaenia with small platelets, eczema, recurrent infections and an increased incidence of autoimmune manifestations and malignancies.

T-cell tolerance

The selective inactivation of T cells that are responsive to particular antigens by deleting such T cells, by paralysing them to produce a state of anergy, or by generating regulatory T cells that restrict their activity. The last two effects can occur concomitantly.

Asymmetric T-cell division

This is a process by which two daughter cells can inherit different amounts of immune receptors and signalling components from a parent cell during T-cell division. It has been suggested that this process occurs because of the polarity of the dividing cell that is associated with immunological synapse formation and that it could specify different fates to the progeny of an individual T cell.

High endothelial venules

(HEVs). Specialized venules that are found in secondary lymphoid organs, except the spleen, and that are important for lymphocyte homing to these sites. Based on constitutive expression of adhesion molecules and chemokines at the luminal surface, HEVs allow continuous transmigration of lymphocytes.

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Bousso, P. T-cell activation by dendritic cells in the lymph node: lessons from the movies. Nat Rev Immunol 8, 675–684 (2008). https://doi.org/10.1038/nri2379

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