Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

How crosstalk at the immune synapse shapes T cell and dendritic cell biologys

Nature Reviews Immunology (2026)Cite this article

Subjects

Abstract

In the context of adaptive immunity, T cells are activated by professional antigen-presenting cells (APCs) in a process that begins with peptide–MHC complexes on the APC being recognized by T cell receptor and CD3 co-receptor complexes on the T cell. This triggers a reorganization of T cell morphology, formation of an immune synapse, and the delivery of signals that ultimately culminate in nuclear activation. The interaction between T cells and APCs, such as dendritic cells (DCs), was originally viewed as a unidirectional information highway in which the APC instructs the T cell. It is now clear that bidirectional crosstalk occurs at the immune synapse and that T cells also shape APC functions. The concept of ‘DC licensing’ originally suggested an instructive role for T cells in modifying DC functions. More recent studies have provided important insight into the changes that occur in DCs during antigen-driven contacts with T cells at the immune synapse. In this Review, we discuss our current understanding of the bidirectional T cell–DC crosstalk that occurs at the IS and its relevance for immune responses and immunotherapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Four key signals for the formation of T cell–DC IS and exploratory scanning.
Fig. 2: T cell signalling, cell polarity and metabolic crosstalk at the IS.
Fig. 3: DC priming and reprogramming at the IS.

Similar content being viewed by others

Data availability

The review manuscript does not contain shared data. Images are accessible by request to the corresponding author.

References

  1. Dustin, M. L. & Choudhuri, K. Signaling and polarized communication across the T cell immunological synapse. Annu. Rev. Cell Dev. Biol. 32, 303–325 (2016).

    Article  CAS  PubMed  Google Scholar 

  2. Huse, M. Mechanoregulation of lymphocyte cytotoxicity. Nat. Rev. Immunol. 25, 680–695 (2025).

    Article  CAS  PubMed  Google Scholar 

  3. Martin-Cofreces, N. B., Baixauli, F. & Sanchez-Madrid, F. Immune synapse: conductor of orchestrated organelle movement. Trends Cell Biol. 24, 61–72 (2014).

    Article  CAS  PubMed  Google Scholar 

  4. Cabeza-Cabrerizo, M., Cardoso, A., Minutti, C. M., Pereira da Costa, M. & Reis e Sousa, C. Dendritic cells revisited. Annu. Rev. Immunol. 39, 131–166 (2021).

    Article  CAS  PubMed  Google Scholar 

  5. Wulfing, C. & Davis, M. M. A receptor/cytoskeletal movement triggered by costimulation during T cell activation. Science 282, 2266–2269 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Monks, C. R., Freiberg, B. A., Kupfer, H., Sciaky, N. & Kupfer, A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82–86 (1998). This seminal paper describes the structure and segregation of receptors at the immune synapse by forming supramolecular activation clusters, a critical process for T cell communication and activation.

    Article  CAS  PubMed  Google Scholar 

  7. Dustin, M. L. et al. A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts. Cell 94, 667–677 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Huang, H., Long, L., Zhou, P., Chapman, N. M. & Chi, H. mTOR signaling at the crossroads of environmental signals and T-cell fate decisions. Immunol. Rev. 295, 15–38 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wulfing, C., Sjaastad, M. D. & Davis, M. M. Visualizing the dynamics of T cell activation: intercellular adhesion molecule 1 migrates rapidly to the T cell/B cell interface and acts to sustain calcium levels. Proc. Natl Acad. Sci. USA 95, 6302–6307 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Montoya, M. C. et al. Role of ICAM-3 in the initial interaction of T lymphocytes and APCs. Nat. Immunol. 3, 159–168 (2002). A description of the initial, exploratory antigen-independent contacts between T cells and APCs by promoting cell adhesion.

    Article  CAS  PubMed  Google Scholar 

  11. Li, J. & Springer, T. A. Integrin extension enables ultrasensitive regulation by cytoskeletal force. Proc. Natl Acad. Sci. USA 114, 4685–4690 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cai, E. et al. Visualizing dynamic microvillar search and stabilization during ligand detection by T cells. Science 356, eaal3118 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Martin-Cofreces, N. B., Valpuesta, J. M. & Sanchez-Madrid, F. T cell asymmetry and metabolic crosstalk can fine-tune immunological synapses. Trends Immunol. 42, 649–653 (2021).

    Article  CAS  PubMed  Google Scholar 

  14. Hu, Y. S., Cang, H. & Lillemeier, B. F. Superresolution imaging reveals nanometer- and micrometer-scale spatial distributions of T-cell receptors in lymph nodes. Proc. Natl Acad. Sci. USA 113, 7201–7206 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Schamel, W. W. et al. Coexistence of multivalent and monovalent TCRs explains high sensitivity and wide range of response. J. Exp. Med. 202, 493–503 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cai, E. et al. T cells use distinct topographical and membrane receptor scanning strategies that individually coalesce during receptor recognition. Proc. Natl Acad. Sci. USA 119, e2203247119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mittelbrunn, M. et al. VLA-4 integrin concentrates at the peripheral supramolecular activation complex of the immune synapse and drives T helper 1 responses. Proc. Natl Acad. Sci. USA 101, 11058–11063 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gil, D., Schamel, W. W., Montoya, M., Sanchez-Madrid, F. & Alarcon, B. Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell 109, 901–912 (2002). The binding of a cognate antigen to the TCR promotes a conformational change in the CD3 complex that exposes proline-rich sequences in the CD3ε chain as a binding site for actin regulator NCK.

    Article  CAS  PubMed  Google Scholar 

  19. Malissen, B. & Bongrand, P. Early T cell activation: integrating biochemical, structural, and biophysical cues. Annu. Rev. Immunol. 33, 539–561 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. Glassman, C. R., Parrish, H. L., Lee, M. S. & Kuhns, M. S. Reciprocal TCR-CD3 and CD4 engagement of a nucleating pMHCII stabilizes a functional receptor macrocomplex. Cell Rep. 22, 1263–1275 (2017).

    Article  Google Scholar 

  21. Horkova, V. et al. Unique roles of co-receptor-bound LCK in helper and cytotoxic T cells. Nat. Immunol. 24, 174–185 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Guy, C. et al. LAG3 associates with TCR-CD3 complexes and suppresses signaling by driving co-receptor-Lck dissociation. Nat. Immunol. 23, 757–767 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lo, W. L. et al. Lck promotes Zap70-dependent LAT phosphorylation by bridging Zap70 to LAT. Nat. Immunol. 19, 733–741 (2018). LCK acts as an adaptor molecule to spread TCR signals upon antigen recognition by bridging ZAP70 kinase to LAT, a substrate for phosphorylation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hartl, F. A. et al. Noncanonical binding of Lck to CD3epsilon promotes TCR signaling and CAR function. Nat. Immunol. 21, 902–913 (2020).

    Article  CAS  PubMed  Google Scholar 

  25. Li, L. et al. Ionic CD3-Lck interaction regulates the initiation of T-cell receptor signaling. Proc. Natl Acad. Sci. USA 114, E5891–E5899 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Nika, K. et al. Constitutively active Lck kinase in T cells drives antigen receptor signal transduction. Immunity 32, 766–777 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Murugesan, S. et al. Formin-generated actomyosin arcs propel T cell receptor microcluster movement at the immune synapse. J. Cell Biol. 215, 383–399 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Johnson, K. G., Bromley, S. K., Dustin, M. L. & Thomas, M. L. A supramolecular basis for CD45 tyrosine phosphatase regulation in sustained T cell activation. Proc. Natl Acad. Sci. USA 97, 10138–10143 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jung, Y., Wen, L., Altman, A. & Ley, K. CD45 pre-exclusion from the tips of T cell microvilli prior to antigen recognition. Nat. Commun. 12, 3872 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lin, J. & Weiss, A. The tyrosine phosphatase CD148 is excluded from the immunologic synapse and down-regulates prolonged T cell signaling. J. Cell Biol. 162, 673–682 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gomez-Moron, A. et al. Human T-cell receptor triggering requires inactivation of Lim kinase-1 by slingshot-1 phosphatase. Commun. Biol. 7, 918 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sanchez-Blanco, C. et al. Protein tyrosine phosphatase PTPN22 regulates LFA-1 dependent Th1 responses. J. Autoimmun. 94, 45–55 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dutta, D. et al. Recruitment of calcineurin to the TCR positively regulates T cell activation. Nat. Immunol. 18, 196–204 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Su, X. et al. Phase separation of signaling molecules promotes T cell receptor signal transduction. Science 352, 595–599 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lillemeier, B. F. et al. TCR and Lat are expressed on separate protein islands on T cell membranes and concatenate during activation. Nat. Immunol. 11, 90–96 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Ashouri, J. F., Lo, W. L., Nguyen, T. T. T., Shen, L. & Weiss, A. ZAP70, too little, too much can lead to autoimmunity. Immunol. Rev. 307, 145–160 (2022).

    Article  CAS  PubMed  Google Scholar 

  37. Rudd, C. E., Taylor, A. & Schneider, H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol. Rev. 229, 12–26 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Leitner, J., Herndler-Brandstetter, D., Zlabinger, G. J., Grubeck-Loebenstein, B. & Steinberger, P. CD58/CD2 Is the primary costimulatory pathway in human CD28-CD8+ T cells. J. Immunol. 195, 477–487 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Williams, C. et al. CD28 and TCR differentially impact naive and memory T cell responses. Discov. Immunol. 4, kyaf006 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sanchez-Lockhart, M., Graf, B. & Miller, J. Signals and sequences that control CD28 localization to the central region of the immunological synapse. J. Immunol. 181, 7639–7648 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Navarro, M. N. & Cantrell, D. A. Serine-threonine kinases in TCR signaling. Nat. Immunol. 15, 808–814 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Thauland, T. J., Koguchi, Y., Dustin, M. L. & Parker, D. C. CD28-CD80 interactions control regulatory T cell motility and immunological synapse formation. J. Immunol. 193, 5894–5903 (2014).

    Article  CAS  PubMed  Google Scholar 

  43. Vignali, D. A., Collison, L. W. & Workman, C. J. How regulatory T cells work. Nat. Rev. Immunol. 8, 523–532 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ecker, M. et al. SNX9-induced membrane tubulation regulates CD28 cluster stability and signalling. eLife 11, e67550 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Matalon, O., Reicher, B. & Barda-Saad, M. Wiskott-Aldrich syndrome protein-dynamic regulation of actin homeostasis: from activation through function and signal termination in T lymphocytes. Immunol. Rev. 256, 10–29 (2013).

    Article  CAS  PubMed  Google Scholar 

  46. Trzupek, D. et al. Discovery of CD80 and CD86 as recent activation markers on regulatory T cells by protein-RNA single-cell analysis. Genome Med. 12, 55 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhao, Y. et al. cis-B7:CD28 interactions at invaginated synaptic membranes provide CD28 co-stimulation and promote CD8+ T cell function and anti-tumor. immunity. Immun. 56, 1187–1203.e1112 (2023).

    Article  CAS  Google Scholar 

  48. Wang, X. D. et al. TCR-induced sumoylation of the kinase PKC-θ controls T cell synapse organization and T cell activation. Nat. Immunol. 16, 1195–1203 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Garcia-Ortiz, A. et al. eNOS S-nitrosylates β-actin on Cys374 and regulates PKC-θ at the immune synapse by impairing actin binding to profilin-1. PLoS Biol. 15, e2000653 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Trefny, M. P. et al. Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy. Nat. Commun. 14, 86 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wei, S. C. et al. Negative co-stimulation constrains T cell differentiation by imposing boundaries on possible cell states. Immunity 50, 1084–1098.e10 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Xu, X. et al. CTLA4 depletes T cell endogenous and trogocytosed B7 ligands via cis-endocytosis. J. Exp. Med. 220, e20221391 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sharpe, A. H. & Pauken, K. E. The diverse functions of the PD1 inhibitory pathway. Nat. Rev. Immunol. 18, 153–167 (2017).

    Article  PubMed  Google Scholar 

  54. Hui, E. et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355, 1428–1433 (2017). PD-1 suppresses T cell function primarily by targeting CD28 phosphorylation through SHP2 and preventing co-stimulation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sanchez-Madrid, F. et al. Three distinct antigens associated with human T-lymphocyte-mediated cytolysis: LFA-1, LFA-2, and LFA-3. Proc. Natl Acad. Sci. USA 79, 7489–7493 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. McArdel, S. L., Terhorst, C. & Sharpe, A. H. Roles of CD48 in regulating immunity and tolerance. Clin. Immunol. 164, 10–20 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kaizuka, Y., Douglass, A. D., Vardhana, S., Dustin, M. L. & Vale, R. D. The coreceptor CD2 uses plasma membrane microdomains to transduce signals in T cells. J. Cell Biol. 185, 521–534 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Demetriou, P. et al. A dynamic CD2-rich compartment at the outer edge of the immunological synapse boosts and integrates signals. Nat. Immunol. 21, 1232–1243 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Delon, J., Stoll, S. & Germain, R. N. Imaging of T-cell interactions with antigen presenting cells in culture and in intact lymphoid tissue. Immunol. Rev. 189, 51–63 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Cyster, J. G. Chemokines and cell migration in secondary lymphoid organs. Science 286, 2098–2102 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  62. Molon, B. et al. T cell costimulation by chemokine receptors. Nat. Immunol. 6, 465–471 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Laufer, J. M., Kindinger, I., Artinger, M., Pauli, A. & Legler, D. F. CCR7 is recruited to the immunological synapse, acts as co-stimulatory molecule and drives LFA-1 clustering for efficient T cell adhesion through ZAP70. Front. Immunol. 9, 3115 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Felce, J. H. et al. Single-molecule, super-resolution, and functional analysis of G protein-coupled receptor behavior within the T cell immunological synapse. Front. Cell Dev. Biol. 8, 608484 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Perez-Martinez, M. et al. F-actin-binding protein drebrin regulates CXCR4 recruitment to the immune synapse. J. Cell Sci. 123, 1160–1170 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Cascio, G. et al. CXCL12 regulates through JAK1 and JAK2 formation of productive immunological synapses. J. Immunol. 194, 5509–5519 (2015).

    Article  CAS  PubMed  Google Scholar 

  67. Kallikourdis, M. et al. The CXCR4 mutations in WHIM syndrome impair the stability of the T-cell immunologic synapse. Blood 122, 666–673 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hickman, A. et al. LFA-1 activation enriches tumor-specific T cells in a cold tumor model and synergizes with CTLA-4 blockade. J. Clin. Invest. 132, e154152 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Geltink, R. I. K., Kyle, R. L. & Pearce, E. L. Unraveling the complex interplay between T cell metabolism and function. Annu. Rev. Immunol. 36, 461–488 (2018).

    Article  CAS  PubMed  Google Scholar 

  70. Schamel, W. W., Alarcon, B. & Minguet, S. The TCR is an allosterically regulated macromolecular machinery changing its conformation while working. Immunol. Rev. 291, 8–25 (2019).

    Article  CAS  PubMed  Google Scholar 

  71. Chen, Y. et al. Cholesterol inhibits TCR signaling by directly restricting TCR-CD3 core tunnel motility. Mol. Cell 82, 1278–1287.e5 (2022).

    Article  CAS  PubMed  Google Scholar 

  72. Wu, W., Shi, X. & Xu, C. Regulation of T cell signalling by membrane lipids. Nat. Rev. Immunol. 16, 690–701 (2016).

    Article  CAS  PubMed  Google Scholar 

  73. Howden, A. J. M. et al. Quantitative analysis of T cell proteomes and environmental sensors during T cell differentiation. Nat. Immunol. 20, 1542–1554 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Martin-Cofreces, N. B. et al. The chaperonin CCT controls T cell receptor-driven 3D configuration of centrioles. Sci. Adv. 6, eabb7242 (2020). CCT chaperonin helps the folding of de novo proteins induced by cognate TCR activation, such as tubulin, thereby regulating immune synapse asymmetric shape adoption and metabolic response.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gomez-Moron, A. et al. Cytosolic protein translation regulates cell asymmetry and function in early TCR activation of human CD8+ T lymphocytes. Front. Immunol. 15, 1411957 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Araki, K. et al. Translation is actively regulated during the differentiation of CD8+ effector T cells. Nat. Immunol. 18, 1046–1057 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ricciardi, S. et al. The translational machinery of human CD4+ T cells is poised for activation and controls the switch from quiescence to metabolic remodeling. Cell Metab. 28, 961 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wolf, T. et al. Dynamics in protein translation sustaining T cell preparedness. Nat. Immunol. 21, 927–937 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Sinclair, L. V. et al. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat. Immunol. 14, 500–508 (2013). TCR activation promotes T cell proliferation and differentiation by upregulating specific amino acid transporters, such as system L-amino acid transporters, which increases the uptake of leucine, and subsequent activation of mTOR, translation and MYC expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Cibrian, D. et al. Targeting L-type amino acid transporter 1 in innate and adaptive T cells efficiently controls skin inflammation. J. Allergy Clin. Immunol. 145, 199–214.e11 (2020).

    Article  CAS  PubMed  Google Scholar 

  81. Cibrian, D. et al. CD69 controls the uptake of L-tryptophan through LAT1-CD98 and AhR-dependent secretion of IL-22 in psoriasis. Nat. Immunol. 17, 985–996 (2016).

    Article  CAS  PubMed  Google Scholar 

  82. Ogbechi, J. et al. LAT1 enables T cell activation under inflammatory conditions. J. Autoimmun. 138, 103031 (2023).

    Article  CAS  PubMed  Google Scholar 

  83. Sinclair, L. V. et al. Antigen receptor control of methionine metabolism in T cells. eLife 8, e44210 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Wu, J. et al. Asparagine enhances LCK signalling to potentiate CD8+ T-cell activation and anti-tumour responses. Nat. Cell Biol. 23, 75–86 (2021).

    Article  CAS  PubMed  Google Scholar 

  85. Hope, H. C. et al. Coordination of asparagine uptake and asparagine synthetase expression modulates CD8+ T cell activation. JCI Insight 6, e137761 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Woehrle, T. et al. Pannexin-1 hemichannel-mediated ATP release together with P2X1 and P2X4 receptors regulate T-cell activation at the immune synapse. Blood 116, 3475–3484 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wang, C. M., Ploia, C., Anselmi, F., Sarukhan, A. & Viola, A. Adenosine triphosphate acts as a paracrine signaling molecule to reduce the motility of T cells. EMBO J. 33, 1354–1364 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Mittelbrunn, M. & Sanchez-Madrid, F. Intercellular communication: diverse structures for exchange of genetic information. Nat. Rev. Mol. Cell Biol. 13, 328–335 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Vivar, O. I. et al. IFT20 controls LAT recruitment to the immune synapse and T-cell activation in vivo. Proc. Natl Acad. Sci. USA 113, 386–391 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Mittelbrunn, M. et al. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat. Commun. 2, 282 (2011).

    Article  PubMed  Google Scholar 

  91. Gomez-Moron, A. et al. End-binding protein 1 regulates the metabolic fate of CD4+ T lymphoblasts and Jurkat T cells and the organization of the mitochondrial network. Front. Immunol. 14, 1197289 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Ruiz-Navarro, J. et al. Formin-like 1β phosphorylation at S1086 is necessary for secretory polarized traffic of exosomes at the immune synapse in Jurkat T lymphocytes. eLife 13, RP96942 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Blas-Rus, N. et al. Aurora A drives early signalling and vesicle dynamics during T-cell activation. Nat. Commun. 7, 11389 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Bustos-Moran, E., Blas-Rus, N., Martin-Cofreces, N. B. & Sanchez-Madrid, F. Microtubule-associated protein-4 controls nanovesicle dynamics and T cell activation. J. Cell Sci. 130, 1217–1223 (2017).

    Article  CAS  PubMed  Google Scholar 

  95. Torralba, D. et al. Priming of dendritic cells by DNA-containing extracellular vesicles from activated T cells through antigen-driven contacts. Nat. Commun. 9, 2658 (2018). Extracellular vesicles enriched in mitochondrial DNA are released at the immune synapse by T cells and taken up by DCs, in which they activate an anti-viral programme through the cGAS–STING pathway.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Saliba, D. G. et al. Composition and structure of synaptic ectosomes exporting antigen receptor linked to functional CD40 ligand from helper T cells. eLife 8, e47528 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Stinchcombe, J. C. et al. Ectocytosis renders T cell receptor signaling self-limiting at the immune synapse. Science 380, 818–823 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Rodriguez-Fernandez, J. L., Riol-Blanco, L., Delgado-Martin, C. & Escribano-Diaz, C. The dendritic cell side of the immunological synapse: exploring terra incognita. Discov. Med. 8, 108–112 (2009).

    PubMed  Google Scholar 

  99. Revy, P., Sospedra, M., Barbour, B. & Trautmann, A. Functional antigen-independent synapses formed between T cells and dendritic cells. Nat. Immunol. 2, 925–931 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Mittelbrunn, M. et al. Imaging of plasmacytoid dendritic cell interactions with T cells. Blood 113, 75–84 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. 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).

    Article  CAS  PubMed  Google Scholar 

  102. Benvenuti, F. et al. Dendritic cell maturation controls adhesion, synapse formation, and the duration of the interactions with naive T lymphocytes. J. Immunol. 172, 292–301 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. de la Fuente, H. et al. Synaptic clusters of MHC class II molecules induced on DCs by adhesion molecule-mediated initial T-cell scanning. Mol. Biol. Cell 16, 3314–3322 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Turley, S. J. et al. Transport of peptide-MHC class II complexes in developing dendritic cells. Science 288, 522–527 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. Benvenuti, F. et al. Requirement of Rac1 and Rac2 expression by mature dendritic cells for T cell priming. Science 305, 1150–1153 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Leithner, A. et al. Dendritic cell actin dynamics control contact duration and priming efficiency at the immunological synapse. J. Cell Biol. 220, e202006081 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Brossard, C. et al. Multifocal structure of the T cell – dendritic cell synapse. Eur. J. Immunol. 35, 1741–1753 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Blanchard, N. et al. Strong and durable TCR clustering at the T/dendritic cell immune synapse is not required for NFAT activation and IFN-γ production in human CD4+ T cells. J. Immunol. 173, 3062–3072 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. Pulecio, J. et al. Cdc42-mediated MTOC polarization in dendritic cells controls targeted delivery of cytokines at the immune synapse. J. Exp. Med. 207, 2719–2732 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Vyas, J. M. et al. Tubulation of class II MHC compartments is microtubule dependent and involves multiple endolysosomal membrane proteins in primary dendritic cells. J. Immunol. 178, 7199–7210 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Rodriguez-Fernandez, J. L., Riol-Blanco, L. & Delgado-Martin, C. What is the function of the dendritic cell side of the immunological synapse. Sci. Signal. 3, re2 (2010).

    Article  PubMed  Google Scholar 

  112. Foster, N., Turnbull, E. L. & Macpherson, G. Migrating lymph dendritic cells contain intracellular CD40 that is mobilized to the immunological synapse during interactions with antigen-specific T lymphocytes. J. Immunol. 189, 5632–5637 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. Fooksman, D. R., Shaikh, S. R., Boyle, S. & Edidin, M. Cutting edge: phosphatidylinositol 4,5-bisphosphate concentration at the APC side of the immunological synapse is required for effector T cell function. J. Immunol. 182, 5179–5182 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Gutierrez-Vazquez, C., Villarroya-Beltri, C., Mittelbrunn, M. & Sanchez-Madrid, F. Transfer of extracellular vesicles during immune cell-cell interactions. Immunol. Rev. 251, 125–142 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Fernandez-Delgado, I., Calzada-Fraile, D. & Sanchez-Madrid, F. Immune regulation by dendritic cell extracellular vesicles in cancer immunotherapy and vaccines. Cancers 12, 3558 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Cespedes, P. F. et al. T-cell trans-synaptic vesicles are distinct and carry greater effector content than constitutive extracellular vesicles. Nat. Commun. 13, 3460 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Benvenuti, F. The dendritic cell synapse: a life dedicated to T cell activation. Front. Immunol. 7, 70 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Alcaraz-Serna, A. et al. Immune synapse instructs epigenomic and transcriptomic functional reprogramming in dendritic cells. Sci. Adv. 7, eabb9965 (2021). DCs reprogramme their gene expression through epigenetic DNA marks after synaptic contacts with T cells, which leads to changes such as enhanced chemotactic cell motility.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Calzada-Fraile, D. et al. Immune synapse formation promotes lipid peroxidation and MHC-I upregulation in licensed dendritic cells for efficient priming of CD8+ T cells. Nat. Commun. 14, 6772 (2023). Immune synaptic contacts with CD4+ T cells modify the metabolic fate of DCs by increasing lipid peroxidation, which fosters antigen loading in MHC class I and cross-presentation to CD8+ T cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hole, C. R. et al. Induction of memory-like dendritic cell responses in vivo. Nat. Commun. 10, 2955 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Guarda, G. et al. L-selectin-negative CCR7- effector and memory CD8+ T cells enter reactive lymph nodes and kill dendritic cells. Nat. Immunol. 8, 743–752 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Hou, W. S. & Van Parijs, L. A Bcl-2-dependent molecular timer regulates the lifespan and immunogenicity of dendritic cells. Nat. Immunol. 5, 583–589 (2004).

    Article  CAS  PubMed  Google Scholar 

  123. Ma, D. Y. & Clark, E. A. The role of CD40 and CD154/CD40L in dendritic cells. Semin. Immunol. 21, 265–272 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Riol-Blanco, L. et al. Immunological synapse formation inhibits, via NF-κB and FOXO1, the apoptosis of dendritic cells. Nat. Immunol. 10, 753–760 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. Giladi, A. et al. Dissecting cellular crosstalk by sequencing physically interacting cells. Nat. Biotechnol. 38, 629–637 (2020). Description of ‘sequencing physically interacting cells’ (PIC-seq) technology to characterize pathways involved in intercellular interaction through omics.

    Article  CAS  PubMed  Google Scholar 

  126. Pasqual, G. et al. Monitoring T cell-dendritic cell interactions in vivo by intercellular enzymatic labelling. Nature 553, 496–500 (2018). Characterization of a CD40–CD40L-based technology to detect ISs in vivo between DCs with CD4+ T cells in LIPSTIC mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Ge, Y. et al. Enzyme-mediated intercellular proximity labeling for detecting cell-cell interactions. J. Am. Chem. Soc. 141, 1833–1837 (2019).

    Article  CAS  PubMed  Google Scholar 

  128. Pasqual, G., Chudnovskiy, A. & Victora, G. D. Monitoring the interaction between dendritic cells and T cells in vivo with LIPSTIC. Methods Mol. Biol. 2618, 71–80 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Campos Canesso, M. C. et al. Identification of antigen-presenting cell-T cell interactions driving immune responses to food. Science 387, eado5088 (2025).

    Article  CAS  PubMed  Google Scholar 

  130. Chudnovskiy, A. et al. Proximity-dependent labeling identifies dendritic cells that drive the tumor-specific CD4+ T cell response. Sci. Immunol. 9, eadq8843 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Nakandakari-Higa, S. et al. Universal recording of immune cell interactions in vivo. Nature 627, 399–406 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Wu, R. & Murphy, K. M. DCs at the center of help: origins and evolution of the three-cell-type hypothesis. J. Exp. Med. 219, e20211519 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ferris, S. T. et al. cDC1 prime and are licensed by CD4+ T cells to induce anti-tumour immunity. Nature 584, 624–629 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Gerner, M. Y., Casey, K. A. & Mescher, M. F. Defective MHC class II presentation by dendritic cells limits CD4 T cell help for antitumor CD8 T cell responses. J. Immunol. 181, 155–164 (2008).

    Article  CAS  PubMed  Google Scholar 

  135. Joffre, O. P., Segura, E., Savina, A. & Amigorena, S. Cross-presentation by dendritic cells. Nat. Rev. Immunol. 12, 557–569 (2012).

    Article  CAS  PubMed  Google Scholar 

  136. Castellino, F. & Germain, R. N. Cooperation between CD4+ and CD8+ T cells: when, where, and how. Annu. Rev. Immunol. 24, 519–540 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. Borst, J., Ahrends, T., Babala, N., Melief, C. J. M. & Kastenmuller, W. CD4+ T cell help in cancer immunology and immunotherapy. Nat. Rev. Immunol. 18, 635–647 (2018).

    Article  CAS  PubMed  Google Scholar 

  138. Smith, C. M. et al. Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity. Nat. Immunol. 5, 1143–1148 (2004).

    Article  CAS  PubMed  Google Scholar 

  139. Bedoui, S., Heath, W. R. & Mueller, S. N. CD4+ T-cell help amplifies innate signals for primary CD8+ T-cell immunity. Immunol. Rev. 272, 52–64 (2016).

    Article  CAS  PubMed  Google Scholar 

  140. Bedenikovic, G., Crouse, J. & Oxenius, A. T-cell help dependence of memory CD8+ T-cell expansion upon vaccinia virus challenge relies on CD40 signaling. Eur. J. Immunol. 44, 115–126 (2013).

    Article  PubMed  Google Scholar 

  141. Janssen, E. M. et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421, 852–856 (2003).

    Article  CAS  PubMed  Google Scholar 

  142. Sun, J. C., Williams, M. A. & Bevan, M. J. CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nat. Immunol. 5, 927–933 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Matthews, K. E. et al. Increasing the survival of dendritic cells in vivo does not replace the requirement for CD4+ T cell help during primary CD8+ T cell responses. J. Immunol. 179, 5738–5747 (2007).

    Article  CAS  PubMed  Google Scholar 

  144. Dingjan, I. et al. Lipid peroxidation causes endosomal antigen release for cross-presentation. Sci. Rep. 6, 22064 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Canton, J. et al. The receptor DNGR-1 signals for phagosomal rupture to promote cross-presentation of dead-cell-associated antigens. Nat. Immunol. 22, 140–153 (2020). DNGR1 priming leads to damage of phagosomes and release of antigens to the cytosol that are processed and loaded onto MHC class I molecules for cross-presentation to cytotoxic CD8+ T cells.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Henry, C. M., Castellanos, C. A. & Reis e Sousa, C. DNGR-1-mediated cross-presentation of dead cell-associated antigens. Semin. Immunol. 66, 101726 (2023).

    Article  CAS  PubMed  Google Scholar 

  147. Gonzales, G. A. et al. The pore-forming apolipoprotein APOL7C drives phagosomal rupture and antigen cross-presentation by dendritic cells. Sci. Immunol. 9, eadn2168 (2024).

    Article  CAS  PubMed  Google Scholar 

  148. Xiong, P. et al. Regulation of expression and trafficking of perforin-2 by LPS and TNF-α. Cell Immunol. 320, 1–10 (2017).

    Article  CAS  PubMed  Google Scholar 

  149. Rodriguez-Silvestre, P. et al. Perforin-2 is a pore-forming effector of endocytic escape in cross-presenting dendritic cells. Science 380, 1258–1265 (2023). Perforin-2 allows endocytic escape of antigens to the cytosol for proteasome processing and loading onto MHC class I molecules in cross-presenting DCs; this helps to initiate anti-viral and anti-tumour immune responses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Al-Alwan, M. M., Rowden, G., Lee, T. D. & West, K. A. Fascin is involved in the antigen presentation activity of mature dendritic cells. J. Immunol. 166, 338–345 (2001).

    Article  CAS  PubMed  Google Scholar 

  151. Chen, J. et al. Strong adhesion by regulatory T cells induces dendritic cell cytoskeletal polarization and contact-dependent lethargy. J. Exp. Med. 214, 327–338 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Eickhoff, S. et al. Robust anti-viral immunity requires multiple distinct T cell-dendritic cell interactions. Cell 162, 1322–1337 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Hor, J. L. et al. Spatiotemporally distinct interactions with dendritic cell subsets facilitates CD4+ and CD8+ T cell activation to localized viral infection. Immunity 43, 554–565 (2015).

    Article  CAS  PubMed  Google Scholar 

  154. Allan, R. S. et al. Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming. Immunity 25, 153–162 (2006).

    Article  CAS  PubMed  Google Scholar 

  155. Yewdall, A. W., Drutman, S. B., Jinwala, F., Bahjat, K. S. & Bhardwaj, N. CD8+ T cell priming by dendritic cell vaccines requires antigen transfer to endogenous antigen presenting cells. PLoS One 5, e11144 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Ruhland, M. K. et al. Visualizing synaptic transfer of tumor antigens among dendritic cells. Cancer Cell 37, 786–799.e5 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Brandi, P. et al. Trained immunity induction by the inactivated mucosal vaccine MV130 protects against experimental viral respiratory infections. Cell Rep. 38, 110184 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Del Fresno, C. et al. The Bacterial mucosal immunotherapy MV130 protects against SARS-CoV-2 infection and improves COVID-19 vaccines immunogenicity. Front. Immunol. 12, 748103 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Cheever, M. A. & Higano, C. S. PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin. Cancer Res. 17, 3520–3526 (2011).

    Article  PubMed  Google Scholar 

  160. Heras-Murillo, I., Adan-Barrientos, I., Galan, M., Wculek, S. K. & Sancho, D. Dendritic cells as orchestrators of anticancer immunity and immunotherapy. Nat. Rev. Clin. Oncol. 21, 257–277 (2024).

    Article  PubMed  Google Scholar 

  161. Wculek, S. K. et al. Dendritic cells in cancer immunology and immunotherapy. Nat. Rev. Immunol. 20, 7–24 (2019).

    Article  PubMed  Google Scholar 

  162. Tanyi, J. L. et al. Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer. Sci. Transl. Med. 10, eaao5931 (2018).

    Article  PubMed  Google Scholar 

  163. Li, Q. et al. A dendritic cell vaccine for both vaccination and neoantigen-reactive T cell preparation for cancer immunotherapy in mice. Nat. Commun. 15, 10419 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Adamik, J. et al. Immuno-metabolic dendritic cell vaccine signatures associate with overall survival in vaccinated melanoma patients. Nat. Commun. 14, 7211 (2023). For DC vaccines, the administration of DCs with increased levels of mitochondrial respiration and fatty acid oxidation (as opposed to highly glycolytic cells) was associated with better patient survival in an NCT01622933 phase I study.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Wieland, A. et al. Defining HPV-specific B cell responses in patients with head and neck cancer. Nature 597, 274–278 (2021).

    Article  CAS  PubMed  Google Scholar 

  166. Fu, C. et al. Plasmacytoid dendritic cells cross-prime naive CD8 T cells by transferring antigen to conventional dendritic cells through exosomes. Proc. Natl Acad. Sci. USA 117, 23730–23741 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Cao, Y. et al. Dendritic cell-mimicking nanoparticles promote mRNA delivery to lymphoid organs. Adv. Sci. 10, e2302423 (2023). The coating of ionizable lipid nanoparticles with DC membranes favours their accumulation in lymphoid organs upon intramuscular or subcutaneous injection and promotes their further adsorption by DCs.

    Article  Google Scholar 

  168. Gu, X., Erb, U., Buchler, M. W. & Zoller, M. Improved vaccine efficacy of tumor exosome compared to tumor lysate loaded dendritic cells in mice. Int. J. Cancer 136, E74–E84 (2014).

    PubMed  Google Scholar 

  169. Carrasco-Padilla, C. et al. T cell activation and effector function in the human Jurkat T cell model. Methods Cell Biol. 178, 25–41 (2023).

    Article  CAS  PubMed  Google Scholar 

  170. Villarroya-Beltri, C. et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat. Commun. 4, 2980 (2013).

    Article  PubMed  Google Scholar 

  171. Garcia-Martin, R. et al. MicroRNA sequence codes for small extracellular vesicle release and cellular retention. Nature 601, 446–451 (2022).

    Article  CAS  PubMed  Google Scholar 

  172. Liu, D. et al. T-B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction. Nature 517, 214–218 (2014).

    Article  PubMed  Google Scholar 

  173. Zaretsky, I. et al. ICAMs support B cell interactions with T follicular helper cells and promote clonal selection. J. Exp. Med. 214, 3435–3448 (2022).

    Article  Google Scholar 

  174. Crotty, S. T follicular helper cell biology: a decade of discovery and diseases. Immunity 50, 1132–1148 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Victora, G. D. & Nussenzweig, M. C. Germinal centers. Annu. Rev. Immunol. 30, 429–457 (2012).

    Article  CAS  PubMed  Google Scholar 

  176. Krautler, N. J. et al. Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells. J. Exp. Med. 214, 1259–1267 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Calado, D. P. et al. The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nat. Immunol. 13, 1092–1100 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Dominguez-Sola, D. et al. The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry. Nat. Immunol. 13, 1083–1091 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Luo, W., Weisel, F. & Shlomchik, M. J. B cell receptor and CD40 signaling are rewired for synergistic induction of the c-Myc transcription factor in germinal center B cells. Immunity 48, 313–326.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Luo, W. et al. IL-21R signal reprogramming cooperates with CD40 and BCR signals to select and differentiate germinal center B cells. Sci. Immunol. 8, eadd1823 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Papa, I. et al. TFH-derived dopamine accelerates productive synapses in germinal centres. Nature 547, 318–323 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Fernandez-Messina, L. et al. Transfer of extracellular vesicle-microRNA controls germinal center reaction and antibody production. EMBO Rep. 21, e48925 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Carisey, A. F., Mace, E. M., Saeed, M. B., Davis, D. M. & Orange, J. S. Nanoscale dynamism of actin enables secretory function in cytolytic cells. Curr. Biol. 28, 489–502.e9 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. de Jesus, M. et al. Single-cell topographical profiling of the immune synapse reveals a biomechanical signature of cytotoxicity. Sci. Immunol. 9, eadj2898 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  185. Zheng, X. et al. Tumors evade immune cytotoxicity by altering the surface topology of NK cells. Nat. Immunol. 24, 802–813 (2023).

    Article  CAS  PubMed  Google Scholar 

  186. Balint, S. et al. Supramolecular attack particles are autonomous killing entities released from cytotoxic T cells. Science 368, 897–901 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Cassioli, C. et al. Activation-induced thrombospondin-4 works with thrombospondin-1 to build cytotoxic supramolecular attack particles. Proc. Natl Acad. Sci. USA 122, e2413866122 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Ambrose, A. R., Hazime, K. S., Worboys, J. D., Niembro-Vivanco, O. & Davis, D. M. Synaptic secretion from human natural killer cells is diverse and includes supramolecular attack particles. Proc. Natl Acad. Sci. USA 117, 23717–23720 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Dosil, S. G. et al. Natural killer (NK) cell-derived extracellular-vesicle shuttled microRNAs control T cell responses. eLife 11, e76319 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Lisci, M. et al. Mitochondrial translation is required for sustained killing by cytotoxic T cells. Science 374, eabe9977 (2021).

    Article  CAS  PubMed  Google Scholar 

  191. Nunez-Andrade, N. et al. HDAC6 regulates the dynamics of lytic granules in cytotoxic T lymphocytes. J. Cell Sci. 129, 1305–1311 (2016).

    Article  CAS  PubMed  Google Scholar 

  192. Bonnet, V. et al. Cancer-on-a-chip model shows that the adenomatous polyposis coli mutation impairs T cell engagement and killing of cancer spheroids. Proc. Natl Acad. Sci. USA 121, e2316500121 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Cazaux, M. et al. Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity. J. Exp. Med. 216, 1038–1049 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Gad, A. Z. et al. Molecular dynamics at immune synapse lipid rafts influence the cytolytic behavior of CAR T cells. Sci. Adv. 11, eadq8114 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Xu, X. et al. Phase separation of chimeric antigen receptor promotes immunological synapse maturation and persistent cytotoxicity. Immunity 57, 2755–2771.e8 (2024).

    Article  CAS  PubMed  Google Scholar 

  196. Gudipati, V. et al. Inefficient CAR-proximal signaling blunts antigen sensitivity. Nat. Immunol. 21, 848–856 (2020).

    Article  CAS  PubMed  Google Scholar 

  197. Martin-Otal, C. et al. Phosphatidylserine as a tumor target for CAR-T cell therapy. J. Immunother. Cancer 13, e009468 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Xiao, Q. et al. Size-dependent activation of CAR-T cells. Sci. Immunol. 7, eabl3995 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Diez-Alonso, L. et al. Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo. Sci. Transl. Med. 16, eadg7962 (2024).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank A. Ramiro, D. Sancho, J. M. Serrador and E. Martín-Gayo for critical reading of the manuscript. This work was supported by CIBER Cardiovascular from the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria del Instituto de Salud Carlos III with co-funding from FEDER) to F.S.-M. and N.B.M.-C.; La Caixa Banking Foundation (LCF/PR/HR23/52430018) to F.S.-M. and N.B.M.-C.; AECC grant PRYCO223002PEIN to F.S.-M.; grants PID2023-147805NB-I00, TERINMUN/CPP2021-008385 and RECYTSEA/PLEC2022-009298 to F.S.-M. and PID2022–141895OB-I00 to N.B.M.-C. funded by MCIN/AEI/10.13039/501100011033, Next Generation EU and “ERDF A way of making Europe”; and Comunidad de Madrid (grant n° S2022/BMD-7209-INTEGRAMUNE-CM) to N.B.M.-C.

Author information

Author notes

  1. Deceased: Diego Calzada-Fraile.

Authors and Affiliations

  1. Department of Immunology, Instituto de Investigación Sanitaria del Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain

    Noa B. Martín-Cófreces, Diego Calzada-Fraile & Francisco Sánchez-Madrid

  2. Videomicroscopy Unit, Instituto de Investigación Sanitaria del Hospital Universitario de la Princesa, Madrid, Spain

    Noa B. Martín-Cófreces

  3. Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain

    Noa B. Martín-Cófreces & Francisco Sánchez-Madrid

Authors
  1. Noa B. Martín-Cófreces
    View author publications

    Search author on:PubMed Google Scholar

  2. Diego Calzada-Fraile
    View author publications

    Search author on:PubMed Google Scholar

  3. Francisco Sánchez-Madrid
    View author publications

    Search author on:PubMed Google Scholar

Contributions

N.B.M.-C. and D.C.-F. contributed to the writing, revision and figure design. F.S.-M. contributed to the writing and revision of the manuscript.

Corresponding author

Correspondence to Francisco Sánchez-Madrid.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Immunology thanks Johnathan Canton, Michael Dustin, Gerone A. Gonzales and Susana Minguet for their contribution to the peer review of this work.

Additional information

Dedication

We wish to dedicate this article to Diego Calzada-Fraile, who devoted invaluable time to studying immune synapses. Unfortunately, he passed away while this article was under revision. Diego possessed an innate talent and tireless thirst for knowledge, which he exhibited both in his scientific pursuits and in his personal life.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Aryl hydrocarbon receptor (AhR)

Cytosolic transcription factor, member of the basic helix–loop–helix/Per-Arnt-Sim (bHLH/PAS) protein family, that regulates gene expression upon translocation to the nucleus in response to aromatic (aryl) hydrocarbons.

cDC1s

Classical type 1 dendritic cells, a subset of dendritic cells characterized by their ability to cross-present antigens.

cDC2s

Classical type 2 dendritic cells, a subset of dendritic cells characterized by their ability to activate CD4+ T cell responses.

Corolla shape

A compartment of the immune synapse where CD2 accumulates in the T cell membrane during its interaction with CD58 in trans, located at the external part of the cell–cell contact with the antigen-presenting cell.

Cross-presentation

A process in which professional antigen-presenting cells present exogenously derived antigenic peptides on MHC class I molecules. The latter are typically loaded with peptides derived from intracellular proteins. Cross-presentation activates CD8+ cytotoxic T lymphocytes to clear infections and tumours bearing these antigens.

Exhausted T cells

A T cell state that is associated with the upregulation of negative regulatory molecules and antigen unresponsiveness. It typically occurs following chronic T cell receptor stimulation with antigen.

Immunoreceptor tyrosine-based activation motifs (ITAMs)

Conserved tandem sequences of four amino acids located in the cytoplasmic tails of immune signalling receptors, such as CD3ε and CD3ζ; they contain a tyrosine that can be phosphorylated.

Inside-out signalling

An intracellular communication process that alters the conformation and function of transmembrane receptors and has a specific effect on their interaction with extracellular ligands.

Licensing

A process in which dendritic cells interaction with activated CD4+ T cells causes the dendritic cells to acquire characteristics that enable them to promote the activation of cytotoxic T lymphocytes.

Memory T cells

Typically long-lived T cells that have previously been activated by cognate antigen. They respond rapidly to subsequent encounters with antigen and can differentiate into effector T cells.

Microdomains

Specialized, small regions within the plasma membrane characterized by the enrichment in specific lipids and proteins, thereby facilitating the formation of distinct functional subdomains.

Naive T cells

T cells that have developed in and exited the thymus but have not yet been activated via their T cell receptor by cognate antigen in the periphery.

Plasmacytoid DCs

A specialized subset of dendritic cells (DCs) that shows lymphoid characteristics and can produce type I interferons. They have been shown to be involved in viral responses and in immune tolerance.

Regulatory T (Treg) cells

A specialized subset of CD4+ T cells that suppresses the activity of other T cells to maintain peripheral tolerance and to limit inflammation. Treg cells also modulate the functions of other cells, including dendritic cells.

SRC homology 3 (SH3)

A small protein domain that binds poly-proline sequences and has a crucial role in protein–protein interactions in cell signalling pathways.

Sumoylation

A reversible post-translational modification of proteins due to the covalent addition of a SUMO (small ubiquitin-related modifier) protein to a lysine residue in a target protein.

Supported-lipid bilayers

Lipidic chemical platforms formed on solid surfaces that have been developed to mimic cell-membrane surfaces by integrating a diverse array of isolated molecules, frequently recombinant proteins or antibodies against bioactive molecules.

WAVE regulatory complex

A complex comprising five components that is essential for proper actin cytoskeletal dynamics and remodelling in eukaryotic cells.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martín-Cófreces, N.B., Calzada-Fraile, D. & Sánchez-Madrid, F. How crosstalk at the immune synapse shapes T cell and dendritic cell biologys. Nat Rev Immunol (2026). https://doi.org/10.1038/s41577-025-01262-2

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41577-025-01262-2

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing