Key Points
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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.
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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.
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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.
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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.
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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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References
von Andrian, U. H. & Mempel, T. R. Homing and cellular traffic in lymph nodes. Nature Rev. Immunol. 3, 867–878 (2003).
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).
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.
Denk, W., Strickler, J. H. & Webb, W. W. Two-photon laser scanning fluorescence microscopy. Science 248, 73–76 (1990).
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).
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).
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).
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).
Bajenoff, M. et al. Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity 25, 989–1001 (2006).
Marzo, A. L. et al. Initial T cell frequency dictates memory CD8+ T cell lineage commitment. Nature Immunol. 6, 793–799 (2005).
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).
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).
Cavanagh, L. L. & Weninger, W. Dendritic cell behaviour in vivo: lessons learned from intravital two-photon microscopy. Immunol. Cell Biol. 86, 428–438 (2008).
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).
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.
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.
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).
Lindquist, R. L. et al. Visualizing dendritic cell networks in vivo. Nature Immunol. 5, 1243–1250 (2004).
Hugues, S. et al. Distinct T cell dynamics in lymph nodes during the induction of tolerance and immunity. Nature Immunol. 5, 1235–1242 (2004).
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.
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).
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).
Tang, Q. et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nature Immunol. 7, 83–92 (2006).
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).
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).
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).
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).
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).
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).
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).
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).
Hugues, S. et al. Dynamic imaging of chemokine-dependent CD8+T cell help for CD8+T cell responses. Nature Immunol. 8, 921–930 (2007).
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).
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).
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.
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).
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).
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).
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).
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).
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).
Harriague, J. & Bismuth, G. Imaging antigen-induced PI3K activation in T cells. Nature Immunol. 3, 1090–1096 (2002).
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).
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).
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.
Dustin, M. L. T-cell activation through immunological synapses and kinapses. Immunol. Rev. 221, 77–89 (2008).
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).
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.
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).
Schneider, H. et al. Reversal of the TCR stop signal by CTLA-4. Science 313, 1972–1975 (2006).
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).
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).
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).
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).
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).
Woodland, D. L. & Dutton, R. W. Heterogeneity of CD4+ and CD8+ T cells. Curr. Opin. Immunol. 15, 336–342 (2003).
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).
Stemberger, C. et al. A single naive CD8+ T cell precursor can develop into diverse effector and memory subsets. Immunity 27, 985–997 (2007).
Chang, J. T. et al. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315, 1687–1691 (2007).
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).
Huang, J. H. et al. Requirements for T lymphocyte migration in explanted lymph nodes. J. Immunol. 178, 7747–7755 (2007).
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).
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).
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).
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).
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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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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Glossary
- Lymph nodes
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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
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(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
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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
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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
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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
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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
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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
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(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
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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
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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
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(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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DOI: https://doi.org/10.1038/nri2379
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