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

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

  • 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
     

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

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • Leitner, J., Herndler-Brandstetter, D., Zlabinger, G. J., Grubeck-Loebenstein, B. & Steinberger, P. CD58/CD2 Is the primary costimulatory pathway in human CD28CD8+ T cells. J. Immunol. 195, 477–487 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

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

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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
     

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

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

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

    Article 
    CAS 
    PubMed 

    Google Scholar
     

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

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

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

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

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

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

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

    Article 
    PubMed 

    Google Scholar
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

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

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

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

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

  • 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
     

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

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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
     

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

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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