Dong, D. et al. Structural basis of assembly of the human T cell receptor–CD3 complex. Nature 573, 546–552 (2019).
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).
Google Scholar
Reth, M. Antigen receptor tail clue. Nature 338, 383–384 (1989).
Google Scholar
Love, P. E. & Hayes, S. M. ITAM-mediated signaling by the T-cell antigen receptor. Cold Spring Harb. Persp. Biol. 2, a002485 (2010).
Pitcher, L. A. & van Oers, N. S. C. T-cell receptor signal transmission: who gives an ITAM? Trends Immunol. 24, 554–560 (2003).
Google Scholar
Letourneur, F. & Klausner, R. D. T-cell and basophil activation through the cytoplasmic tail of T-cell-receptor ζ family proteins. Proc. Natl Acad. Sci. USA 88, 8905–8909 (1991).
Google Scholar
Irving, B. A. & Weiss, A. The cytoplasmic domain of the T cell receptor ζ chain is sufficient to couple to receptor-associated signal transduction pathways. Cell 64, 891–901 (1991).
Google Scholar
Romeo, C. & Seed, B. Cellular immunity to HIV activated by CD4 fused to T cell or Fc receptor polypeptides. Cell 64, 1037–1046 (1991).
Google Scholar
Rafiq, S., Hackett, C. S. & Brentjens, R. J. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat. Rev. Clin. Oncol. 17, 147–167 (2020).
Google Scholar
Majzner, R. G. et al. GD2–CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022).
Google Scholar
Huang, J., Huang, X. & Huang, J. CAR-T cell therapy for hematological malignancies: limitations and optimization strategies. Front. Immunol. 13, 1019115 (2022).
Google Scholar
Morris, E. C., Neelapu, S. S., Giavridis, T. & Sadelain, M. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat. Rev. Immunol. 22, 85–96 (2022).
Google Scholar
Swamy, M. et al. A cholesterol-based allostery model of T cell receptor phosphorylation. Immunity 44, 1091–1101 (2016).
Google Scholar
Courtney, A. H., Lo, W. L. & Weiss, A. TCR signaling: mechanisms of initiation and propagation. Trends Biochem. Sci. 43, 108–123 (2018).
Google Scholar
Aivazian, D. & Stern, L. J. Phosphorylation of T cell receptor ζ is regulated by a lipid dependent folding transition. Nat. Struct. Biol. 7, 1023–1026 (2000).
Google Scholar
Zhang, H., Cordoba, S.-P., Dushek, O. & van der Merwe, P. A. Basic residues in the T-cell receptor ζ cytoplasmic domain mediate membrane association and modulate signaling. Proc. Natl Acad. Sci. USA 108, 19323–19328 (2011).
Google Scholar
Xu, C. et al. Regulation of T cell receptor activation by dynamic membrane binding of the CD3ε cytoplasmic tyrosine-based motif. Cell 135, 702–713 (2008).
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).
Google Scholar
Wu, W. et al. Multiple signaling roles of CD3ε and its application in CAR-T cell therapy. Cell 182, 855–871.e23 (2020).
Google Scholar
von Essen, M. et al. The CD3 γ leucine-based receptor-sorting motif is required for efficient ligand-mediated TCR down-regulation. J. Immunol. 168, 4519–4523 (2002).
Google Scholar
Janeway, C. A. Ligands for the T-cell receptor: hard times for avidity models. Immunol. Today 16, 223–225 (1995).
Google Scholar
Lever, M., Maini, P. K., van der Merwe, P. A. & Dushek, O. Phenotypic models of T cell activation. Nat. Rev. Immunol. 14, 619–629 (2014).
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).
Google Scholar
Minguet, S., Swamy, M., Alarcón, B., Luescher, I. F. & Schamel, W. W. A. Full activation of the T cell receptor requires both clustering and conformational changes at CD3. Immunity 26, 43–54 (2007).
Google Scholar
Cochran, J. R., Cameron, T. O. & Stern, L. J. The relationship of MHC-peptide binding and T cell activation probed using chemically defined MHC class II oligomers. Immunity 12, 241–250 (2000).
Google Scholar
Boniface, J. J. et al. Initiation of signal transduction through the T cell receptor requires the multivalent engagement of peptide/MHC ligands (corrected). Immunity 9, 459–466 (1998).
Google Scholar
Davis, S. J. & van der Merwe, P. A. The kinetic-segregation model: TCR triggering and beyond. Nat. Immunol. 7, 803–809 (2006).
Google Scholar
Springer, T. A. Adhesion receptors of the immune system. Nature 346, 425–434 (1990).
Google Scholar
Cordoba, S.-P. et al. The large ectodomains of CD45 and CD148 regulate their segregation from and inhibition of ligated T-cell receptor. Blood 121, 4295–4302 (2013).
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).
Google Scholar
Acuto, O. T-cell virtuosity in “knowing thyself”. Front. Immunol. 15, 1343575 (2024).
Google Scholar
Hartl, F. A. et al. Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function. Nat. Immunol. 21, 902–913 (2020).
Google Scholar
Gil, D., Schamel, W. W. A., Montoya, M., Sánchez-Madrid, F. & Alarcón, B. Recruitment of Nck by CD3ε reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell 109, 901–912 (2002).
Google Scholar
Blanco, R., Borroto, A., Schamel, W., Pereira, P. & Alarcon, B. Conformational changes in the T cell receptor differentially determine T cell subset development in mice. Sci. Signal. 7, ra115 (2014).
Google Scholar
Risueño, R. M., van Santen, H. M. & Alarcón, B. A conformational change senses the strength of T cell receptor–ligand interaction during thymic selection. Proc. Natl Acad. Sci. USA 103, 9625–9630 (2006).
Google Scholar
Lee, M. S. et al. A mechanical switch couples T cell receptor triggering to the cytoplasmic juxtamembrane regions of CD3ζζ. Immunity 43, 227–239 (2015).
Google Scholar
Sušac, L. et al. Structure of a fully assembled tumor-specific T cell receptor ligated by pMHC. Cell 185, 3201–3213.e19 (2022).
Google Scholar
Notti, R. Q. et al. The resting state of the human T-cell receptor. Preprint at bioRxiv https://doi.org/10.1101/2023.08.22.554360 (2023).
van Eerden, F. J. et al. TCR binding to a peptide-MHC complex raises a drawbridge for CD3 cross-membrane signaling. preprint at bioRxiv https://doi.org/10.1101/2022.07.27.501668 (2022).
Molnár, E. et al. Cholesterol and sphingomyelin drive ligand-independent T-cell antigen receptor nanoclustering. J. Biol. Chem. 287, 42664–42674 (2012).
Google Scholar
Pathan-Chhatbar, S. et al. Direct regulation of the T cell antigen receptor’s activity by cholesterol. Front. Cell Dev. Biol. 8, 615996 (2021).
Google Scholar
Shi, X. et al. Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids. Nature 493, 111–115 (2013).
Google Scholar
Deford-Watts, L. M. et al. The cytoplasmic tail of the T cell receptor CD3ε subunit contains a phospholipid-binding motif that regulates T cell functions. J. Immunol. 183, 1055–1064 (2009).
Google Scholar
Xu, X., Li, H. & Xu, C. Structural understanding of T cell receptor triggering. Cell. Mol. Immunol. 17, 193–202 (2020).
Google Scholar
Hem, C. D. et al. T cell specific adaptor protein (TSAd) promotes interaction of Nck with Lck and SLP-76 in T cells. Cell. Commun. Signal. 13, 31 (2015).
Google Scholar
Velasco Cárdenas, R. M.-H. et al. Harnessing CD3 diversity to optimize CAR T cells. Nat. Immunol. 24, 2135–2149 (2023).
Google Scholar
Horkova, V. et al. Unique roles of co-receptor-bound LCK in helper and cytotoxic T cells. Nat. Immunol. 24, 174–185 (2023).
Google Scholar
June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018).
Google Scholar
Honikel, M. M. & Olejniczak, S. H. Co-stimulatory receptor signaling in CAR-T cells. Biomolecules 12, 1303 (2022).
Google Scholar
Hege, K. M. et al. Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer. J. Immunother. Cancer 5, 22 (2017).
Google Scholar
Till, B. G. et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 112, 2261–2271 (2008).
Google Scholar
Brocker, T. Chimeric Fv-ζ or Fv-ε receptors are not sufficient to induce activation or cytokine production in peripheral T cells. Blood 96, 1999–2001 (2000).
Google Scholar
Asmamaw Dejenie, T. et al. Current updates on generations, approvals, and clinical trials of CAR T-cell therapy. Hum. Vaccin. Immunother. 18, 2114254 (2022).
Google Scholar
Wang, H., Song, X., Shen, L., Wang, X. & Xu, C. Exploiting T cell signaling to optimize engineered T cell therapies. Trends Cancer 8, 123–134 (2022).
Google Scholar
Ajina, A. & Maher, J. Strategies to address chimeric antigen receptor tonic signaling. Mol. Cancer Ther. 17, 1795–1815 (2018).
Google Scholar
Salzer, B. et al. Engineering AvidCARs for combinatorial antigen recognition and reversible control of CAR function. Nat. Commun. 11, 4166 (2020).
Google Scholar
Wang, H., Huang, Y. & Xu, C. Charging CAR by electrostatic power. Immunol. Rev. 320, 138–146 (2023).
Google Scholar
Nieba, L., Honegger, A., Krebber, C. & Plückthun, A. Disrupting the hydrophobic patches at the antibody variable/constant domain interface: improved in vivo folding and physical characterization of an engineered scFv fragment. Protein Eng. 10, 435–444 (1997).
Google Scholar
Atwell, J. L. et al. scFv multimers of the anti-neuraminidase antibody NC10: length of the linker between VH and VL domains dictates precisely the transition between diabodies and triabodies. Protein Eng. 12, 597–604 (1999).
Google Scholar
Choudhuri, K., Wiseman, D., Brown, M. H., Gould, K. & van der Merwe, P. A. T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand. Nature 436, 578–582 (2005).
Google Scholar
Srivastava, S. & Riddell, S. R. Engineering CAR-T cells: design concepts. Trends Immunol. 36, 494–502 (2015).
Google Scholar
Xiao, Q. et al. Size-dependent activation of CAR-T cells. Sci. Immunol. 7, eabl3995 (2022).
Google Scholar
Filby, A. et al. Fyn regulates the duration of TCR engagement needed for commitment to effector function. J. Immunol. 179, 4635–4644 (2007).
Google Scholar
Wu, L. et al. CD28–CAR-T cell activation through FYN kinase signaling rather than LCK enhances therapeutic performance. Cell. Rep. Med. 4, 100917 (2023).
Google Scholar
Purbhoo, M. A., Irvine, D. J., Huppa, J. B. & Davis, M. M. T cell killing does not require the formation of a stable mature immunological synapse. Nat. Immunol. 5, 524–530 (2004).
Google Scholar
Irvine, D. J., Purbhoo, M. A., Krogsgaard, M. & Davis, M. M. Direct observation of ligand recognition by T cells. Nature 419, 845–849 (2002).
Google Scholar
Burton, J. et al. Inefficient exploitation of accessory receptors reduces the sensitivity of chimeric antigen receptors. Proc. Natl Acad. Sci. USA 120, e2216352120 (2023).
Google Scholar
Gudipati, V. et al. Inefficient CAR-proximal signaling blunts antigen sensitivity. Nat. Immunol. 21, 848–856 (2020).
Google Scholar
James, S. E. et al. Mathematical modeling of chimeric TCR triggering predicts the magnitude of target lysis and its impairment by TCR downmodulation. J. Immunol. 184, 4284–4294 (2010).
Google Scholar
Harris, D. T. et al. Comparison of T cell activities mediated by human TCRs and CARs that use the same recognition domains. J. Immunol. 200, 1088–1100 (2018).
Google Scholar
Mansilla-Soto, J. et al. HLA-independent T cell receptors for targeting tumors with low antigen density. Nat. Med. 28, 345–352 (2022).
Google Scholar
Walker, A. J. et al. Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase. Mol. Ther. 25, 2189–2201 (2017).
Google Scholar
Salter, A. I. et al. Comparative analysis of TCR and CAR signaling informs CAR designs with superior antigen sensitivity and in vivo function. Sci. Signal. 14, eabe2606 (2021).
Google Scholar
Harrer, D. C. et al. Fine-tuning the antigen sensitivity of CAR T cells: emerging strategies and current challenges. Front. Immunol. 14, 1321596 (2023).
Google Scholar
Qian, D., Griswold-Prenner, I., Rosner, M. R. & Fitch, F. W. Multiple components of the T cell antigen receptor complex become tyrosine-phosphorylated upon activation. J. Biol. Chem. 268, 4488–4493 (1993).
Google Scholar
Baniyash, M., Garcia-Morales, P., Luong, E., Samelson, L. E. & Klausner, R. D. The T cell antigen receptor ζ chain is tyrosine phosphorylated upon activation. J. Biol. Chem. 263, 18225–18230 (1988).
Google Scholar
Chylek, L. A. et al. Phosphorylation site dynamics of early T-cell receptor signaling. PLoS ONE 9, e104240 (2014).
Google Scholar
Holst, J. et al. Scalable signaling mediated by T cell antigen receptor-CD3 ITAMs ensures effective negative selection and prevents autoimmunity. Nat. Immunol. 9, 658–666 (2008).
Google Scholar
Pitcher, L. A. et al. The CD3 γε/δε signaling module provides normal T cell functions in the absence of the TCR ζ immunoreceptor tyrosine-based activation motifs. Eur. J. Immunol. 35, 3643–3654 (2005).
Google Scholar
Bettini, M. L. et al. Cutting edge: CD3 ITAM diversity is required for optimal TCR signaling and thymocyte development. J. Immunol. 199, 1555–1560 (2017).
Google Scholar
Osman, N., Turner, H., Lucas, S., Reif, K. & Cantrell, D. A. The protein interactions of the immunoglobulin receptor family tyrosine-based activation motifs present in the T cell receptor ζ subunits and the CD3 γ, δ and ε chains. Eur. J. Immunol. 26, 1063–1068 (1996).
Google Scholar
Sunder-Plassmann, R., Lialios, F., Madsen, M., Koyasu, S. & Reinherz, E. L. Functional analysis of immunoreceptor tyrosine-based activation motif (ITAM)-mediated signal transduction: the two YxxL segments within a single CD3ζ-ITAM are functionally distinct. Eur. J. Immunol. 27, 2001–2009 (1997).
Google Scholar
Guirado, M. et al. Phosphorylation of the N-terminal and C-terminal CD3-ε–ITAM tyrosines is differentially regulated in T cells. Biochem. Biophys. Res. Commun. 291, 574–581 (2002).
Google Scholar
Paensuwan, P. et al. Nck binds to the T cell antigen receptor using its SH3.1 and SH2 domains in a cooperative manner, promoting TCR functioning. J. Immunol. 196, 448–458 (2016).
Google Scholar
Kesti, T. et al. Reciprocal regulation of SH3 and SH2 domain binding via tyrosine phosphorylation of a common site in CD3ε. J. Immunol. 179, 878–885 (2007).
Google Scholar
Zhao, Y. et al. A herceptin-based chimeric antigen receptor with modified signaling domains leads to enhanced survival of transduced T lymphocytes and antitumor activity. J. Immunol. 183, 5563–5574 (2009).
Google Scholar
Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017).
Google Scholar
Long, A. H. et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat. Med. 21, 581–590 (2015).
Google Scholar
James, J. R. Tuning ITAM multiplicity on T cell receptors can control potency and selectivity to ligand density. Sci. Signal. 11, eaan1088 (2018).
Google Scholar
Majzner, R. G. et al. Tuning the antigen density requirement for CAR T-cell activity. Cancer Discov. 10, 702–723 (2020).
Google Scholar
Feucht, J. et al. Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. Nat. Med. 25, 82–88 (2019).
Google Scholar
Kochenderfer, J. N., Yu, Z., Frasheri, D., Restifo, N. P. & Rosenberg, S. A. Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood 116, 3875–3886 (2010).
Google Scholar
Guo, X. et al. Lipid-dependent conformational dynamics underlie the functional versatility of T-cell receptor. Cell Res. 27, 505–525 (2017).
Google Scholar
Gagnon, E., Schubert, D. A., Gordo, S., Chu, H. H. & Wucherpfennig, K. W. Local changes in lipid environment of TCR microclusters regulate membrane binding by the CD3ε cytoplasmic domain. J. Exp. Med. 209, 2423–2439 (2012).
Google Scholar
Li, H., Yan, C., Guo, J. & Xu, C. Ionic protein–lipid interactions at the plasma membrane regulate the structure and function of immunoreceptors. Adv. Immunol. 144, 65–85 (2019).
Google Scholar
Baeuerle, P. A. et al. Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response. Nat. Commun. 10, 2087 (2019).
Google Scholar
Gomes-Silva, D. et al. Tonic 4-1BB costimulation in chimeric antigen receptors impedes T cell survival and is vector-dependent. Cell. Rep. 21, 17–26 (2017).
Google Scholar
DeFord-Watts, L. M., Young, J. A., Pitcher, L. A. & van Oers, N. S. C. The membrane-proximal portion of CD3 ε associates with the serine/threonine kinase GRK2. J. Biol. Chem. 282, 16126–16134 (2007).
Google Scholar
Dobbins, J. et al. Binding of the cytoplasmic domain of CD28 to the plasma membrane inhibits Lck recruitment and signaling. Sci. Signal. 9, ra75 (2016).
Google Scholar
Yang, W. et al. Dynamic regulation of CD28 conformation and signaling by charged lipids and ions. Nat. Struct. Mol. Biol. 24, 1081–1092 (2017).
Google Scholar
Hartl, F. A. et al. Cooperative interaction of nck and lck orchestrates optimal TCR signaling. Cells 10, 834 (2021).
Google Scholar
Tailor, P. et al. The proline-rich sequence of CD3ε as an amplifier of low-avidity TCR signaling. J. Immunol. 181, 243–255 (2008).
Google Scholar
Borroto, A. et al. First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases. Sci. Transl. Med. 8, 370ra184 (2016).
Google Scholar
Borroto, A. et al. Nck recruitment to the TCR required for ZAP70 activation during thymic development. J. Immunol. 190, 1103–1112 (2013).
Google Scholar
Martin-Blanco, N. et al. CD3ε recruits Numb to promote TCR degradation. Int. Immunol. 28, 127–137 (2016).
Google Scholar
Mingueneau, M. et al. The proline-rich sequence of CD3ε controls T cell antigen receptor expression on and signaling potency in preselection CD4+CD8+ thymocytes. Nat. Immunol. 9, 522–532 (2008).
Google Scholar
Borroto, A. et al. Relevance of Nck–CD3ε interaction for T cell activation in vivo. J. Immunol. 192, 2042–2053 (2014).
Google Scholar
Szymczak, A. L. et al. The CD3ε proline-rich sequence, and its interaction with Nck, is not required for T cell development and function. J. Immunol. 175, 270–275 (2005).
Google Scholar
Göbel, T. W. & Dangy, J. P. Evidence for a stepwise evolution of the CD3 family. J. Immunol. 164, 879–883 (2000).
Google Scholar
Dietrich, J., Hou, X., Wegener, A. M. & Geisler, C. CD3 γ contains a phosphoserine-dependent di-leucine motif involved in down-regulation of the T cell receptor. EMBO J. 13, 2156–2166 (1994).
Google Scholar
Boding, L. et al. TCR down-regulation controls T cell homeostasis. J. Immunol. 183, 4994–5005 (2009).
Google Scholar
Bonefeld, C. M. et al. TCR down-regulation controls virus-specific CD8+ T cell responses. J. Immunol. 181, 7786–7799 (2008).
Google Scholar
Kolanus, W., Romeo, C. & Seed, B. T cell activation by clustered tyrosine kinases. Cell 74, 171–183 (1993).
Google Scholar
Fitzer-Attas, C. J., Schindler, D. G., Waks, T. & Eshhar, Z. Harnessing Syk family tyrosine kinases as signaling domains for chimeric single chain of the variable domain receptors: optimal design for T cell activation. J. Immunol. 160, 145–154 (1998).
Google Scholar
Tousley, A. M. et al. Co-opting signalling molecules enables logic-gated control of CAR T cells. Nature 615, 507–516 (2023).
Google Scholar
Balagopalan, L. et al. Generation of antitumor chimeric antigen receptors incorporating T cell signaling motifs. Sci. Signal. 17, eadp8569 (2024).
Google Scholar
Liu, Y. et al. Chimeric STAR receptors using TCR machinery mediate robust responses against solid tumors. Sci. Transl. Med. 13, eabb5191 (2021).
Google Scholar
Xu, Y. et al. A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release. Cell Discov. 4, 62 (2018).
Google Scholar
Helsen, C. W. et al. The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity. Nat. Commun. 9, 3049 (2018).
Google Scholar
Schamel, W. W. A. et al. Coexistence of multivalent and monovalent TCRs explains high sensitivity and wide range of response. J. Exp. Med. 202, 493–503 (2005).
Google Scholar
Minguet, S. et al. The extracellular part of ζ is buried in the T cell antigen receptor complex. Immunol. Lett. 116, 203–210 (2008).
Google Scholar
Ding, J. et al. Mesothelin-targeting T cells bearing a novel T cell receptor fusion construct (TRuC) exhibit potent antitumor efficacy against solid tumors. Oncoimmunology 12, 2182058 (2023).
Google Scholar
Rana, J. et al. CAR- and TRuC-redirected regulatory T cells differ in capacity to control adaptive immunity to FVIII. Mol. Ther. 29, 2660–2676 (2021).
Google Scholar
Sun, Y. et al. Chimeric anti-GPC3 sFv-CD3ε receptor-modified T cells with IL7 co-expression for the treatment of solid tumors. Mol. Ther. Oncolyt. 25, 160–173 (2022).
Google Scholar
Zhang, Z. et al. Treating solid tumors with TCR-based chimeric antigen receptor targeting extra domain B-containing fibronectin. J. Immunother. Cancer 11, e007199 (2023).
Google Scholar
Birtel, M. et al. A TCR-like CAR promotes sensitive antigen recognition and controlled T-cell expansion upon mRNA vaccination. Cancer Res. Commun. 2, 827–841 (2022).
Google Scholar
Chen, Z. et al. Antibody-based binding domain fused to TCRγ chain facilitates T cell cytotoxicity for potent anti-tumor response. Oncogenesis 12, 33 (2023).
Google Scholar
Lesch, S. et al. PD-1-CD28 fusion protein strengthens mesothelin-specific TRuC T cells in preclinical solid tumor models. Cell. Oncol. 46, 227–235 (2023).
Google Scholar
Juraske, C. et al. Reprogramming of human γδ T cells by expression of an anti-CD19 TCR fusion construct (εTRuC) to enhance tumor killing. J. Leuk. Biol. 115, 293–305 (2024).
Google Scholar
Li, C. et al. Novel CD19-specific γ/δ TCR-T cells in relapsed or refractory diffuse large B-cell lymphoma. J. Hematol. Oncol. 16, 5 (2023).
Google Scholar
Kuwana, Y. et al. Expression of chimeric receptor composed of immunoglobulin-derived V resions and T-cell receptor-derived C regions. Biochem. Biophys. Res. Commun. 149, 960–968 (1987).
Google Scholar
Wang, J. et al. A novel adoptive synthetic TCR and antigen receptor (STAR) T-Cell therapy for B-cell acute lymphoblastic leukemia. Am. J. Hematol. 97, 992–1004 (2022).
Google Scholar
Hassan, R. et al. Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1/2 trial interim results. Nat. Med. 29, 2099–2109 (2023).
Google Scholar
He, P. et al. A novel antibody-TCR (AbTCR) T-cell therapy is safe and effective against CD19-positive relapsed/refractory B-cell lymphoma. J. Cancer Res. Clin. Oncol. 149, 2757–2769 (2023).
Google Scholar
Singh, N., Perazzelli, J., Grupp, S. A. & Barrett, D. M. Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies. Sci. Transl. Med. 8, 320ra3 (2016).
Google Scholar
Fraietta, J. A. et al. Biomarkers of response to anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in patients with chronic lymphocytic leukemia. Blood 128, 57–57 (2016).
Google Scholar
Frigault, M. J. et al. Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells. Cancer Immunol. Res. 3, 356–367 (2015).
Google Scholar
Feucht, J. & Sadelain, M. Function and evolution of the prototypic CD28ζ and 4-1BBζ chimeric antigen receptors. Immunooncol. Technol. 8, 2–11 (2020).
Google Scholar
Chen, J. et al. Tuning charge density of chimeric antigen receptor optimizes tonic signaling and CAR-T cell fitness. Cell Res. 33, 341–354 (2023).
Google Scholar
Sarén, T. et al. Complementarity-determining region clustering may cause CAR-T cell dysfunction. Nat. Commun. 14, 4732 (2023).
Google Scholar
Hudecek, M. et al. The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity. Cancer Immunol. Res. 3, 125–135 (2015).
Google Scholar
Hombach, A., Hombach, A. A. & Abken, H. Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc ‘spacer’ domain in the extracellular moiety of chimeric antigen receptors avoids ‘off-target’ activation and unintended initiation of an innate immune response. Gene Ther. 17, 1206–1213 (2010).
Google Scholar
Watanabe, N. et al. Fine-tuning the CAR spacer improves T-cell potency. Oncoimmunology 5, e1253656 (2016).
Google Scholar
Myers, D. R., Zikherman, J. & Roose, J. P. Tonic signals: why do lymphocytes bother? Trends Immunol. 38, 844–857 (2017).
Google Scholar
Stefanová, I. et al. TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat. Immunol. 4, 248–254 (2003).
Google Scholar
Dustin, M. L. & Choudhuri, K. Signaling and polarized communication across the T cell immunological synapse. Annu. Rev. Cell Dev. Biol. 32, 303–325 (2016).
Google Scholar
Davenport, A. J. et al. Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity. Proc. Natl Acad. Sci. USA 115, E2068–E2076 (2018).
Google Scholar
Gross, G., Waks, T. & Eshhar, Z. Expression of immunoglobulin-T-cell receptor 960 chimeric molecules as functional receptors with antibody-type specificity. Proc. Natl Acad. Sci. USA 86, 10024–10028 (1989).
Google Scholar
Becker, M. L. et al. Expression of a hybrid immunoglobulin-T cell receptor protein in 963 transgenic mice. Cell 58, 911–921 (1989).
Google Scholar
Goverman, J. et al. Chimeric immunoglobulin-T cell receptor proteins form functional 965 receptors: implications for T cell receptor complex formation and activation. Cell 60, 966 929–39 (1990).
Google Scholar
Eshhar, Z., Waks, T., Gross, G. & Schindler, D. G. Specific activation and targeting of 968 cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding 969 domains and the γ or ζ subunits of the immunoglobulin and T-cell receptors. Proc. Natl Acad. Sci. USA 90, 720–724 (1993).
Google Scholar
McGuinness, R. P. et al. Anti-tumor activity of human T cells expressing the CC49-972 ζ chimeric immune receptor. Hum. Gene Ther. 10, 165–173 (1999).
Google Scholar
Maher, J., Brentjens, R. J., Gunset, G., Rivière, I. & Sadelain, M. Human T980 lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ 981 /CD28 receptor. Nat. Biotechnol. 20, 70–75 (2002).
Google Scholar
Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen 977 receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–33 978 (2011).
Google Scholar
Imai, C. et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18, 676–684 (2004).
Google Scholar
He, C. et al. CD19 CAR antigen engagement mechanisms and affinity tuning. Sci. Immunol. 8, eadf1426 (2023).
Google Scholar
Ghorashian, S. et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat. Med. 25, 1408–1414 (2019).
Google Scholar
Valitutti, S., Müller, S., Cella, M., Padovan, E. & Lanzavecchia, A. Serial triggering of many T-cell receptors by a few peptide–MHC complexes. Nature 375, 148–151 (1995).
Google Scholar
Watanabe, K. et al. Target antigen density governs the efficacy of anti-CD20-CD28-CD3 ζ chimeric antigen receptor-modified effector CD8+ T cells. J. Immunol. 194, 911–920 (2015).
Google Scholar
Feng, Y. et al. Mechanosensing drives acuity of αβ T-cell recognition. Proc. Natl Acad. Sci. USA 114, E8204–E8213 (2017).
Google Scholar