T Cell Activation Machinery: Form and Function in Natural and Engineered Immune Receptors

The impressive success of chimeric antigen receptor (CAR)-T cell therapies in treating advanced B-cell malignancies has spurred a frenzy of activity aimed at developing CAR-T therapies for other cancers, particularly solid tumors, and optimizing engineered T cells for maximum clinical benefit in many different disease contexts. A rapidly growing body of design work is examining every modular component of traditional single-chain CARs as well as expanding out into many new and innovative engineered immunoreceptor designs that depart from this template. New approaches to immune cell and receptor engineering are being reported with rapidly increasing frequency, and many recent high-quality reviews (including one in this special issue) provide comprehensive coverage of the history and current state of the art in CAR-T and related cellular immunotherapies. In this review, we step back to examine our current understanding of the structure-function relationships in natural and engineered lymphocyte-activating receptors, with an eye towards evaluating how well the current-generation CAR designs recapitulate the most desirable features of their natural counterparts. We identify key areas that we believe are under-studied and therefore represent opportunities to further improve our grasp of form and function in natural and engineered receptors and to rationally design better therapeutics.

[1]  Martin Wiedmann,et al.  The Organizing Principle in the Formation of the T Cell Receptor-CD3 Complex , 2002, Cell.

[2]  E. Reinherz,et al.  Mechanisms Contributing to T Cell Receptor Signaling and Assembly Revealed by the Solution Structure of an Ectodomain Fragment of the CD3ϵγ Heterodimer , 2001, Cell.

[3]  P. Linsley,et al.  CTLA-4 is a second receptor for the B cell activation antigen B7 , 1991, The Journal of experimental medicine.

[4]  M. Sadelain,et al.  Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[5]  J. Trapani,et al.  Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity , 2018, Proceedings of the National Academy of Sciences.

[6]  Mark M. Davis,et al.  TCR Signaling Emerges from the Sum of Many Parts , 2012, Front. Immun..

[7]  P. Lograsso,et al.  Mechanism of activation for Zap-70 catalytic activity. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[8]  J. Bonifacino,et al.  Transmembrane helical interactions: zeta chain dimerization and functional association with the T cell antigen receptor. , 1992, The EMBO journal.

[9]  Lieping Chen,et al.  Molecular mechanisms of T cell co-stimulation and co-inhibition , 2013, Nature Reviews Immunology.

[10]  Arthur Weiss,et al.  Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor , 1992, Cell.

[11]  H Clevers,et al.  The T cell receptor/CD3 complex: a dynamic protein ensemble. , 1988, Annual review of immunology.

[12]  Jim Miller,et al.  The CD28 Transmembrane Domain Contains an Essential Dimerization Motif , 2020, Frontiers in Immunology.

[13]  James J. Chou,et al.  The Structure of the ζζ Transmembrane Dimer Reveals Features Essential for Its Assembly with the T Cell Receptor , 2006, Cell.

[14]  J. Myklebust,et al.  Tuning the Antigen Density Requirement for CAR T Cell Activity. , 2020, Cancer discovery.

[15]  J. Godec,et al.  Binding of the cytoplasmic domain of CD28 to the plasma membrane inhibits Lck recruitment and signaling , 2016, Science Signaling.

[16]  E. Reinherz,et al.  Developmentally regulated glycosylation of the CD8alphabeta coreceptor stalk modulates ligand binding. , 2001, Cell.

[17]  K. Wucherpfennig,et al.  The T cell receptor: critical role of the membrane environment in receptor assembly and function. , 2005, Annual review of immunology.

[18]  G. Adams,et al.  T Cell Activation by Antibody-Like Immunoreceptors: Increase in Affinity of the Single-Chain Fragment Domain above Threshold Does Not Increase T Cell Activation against Antigen-Positive Target Cells but Decreases Selectivity1 , 2004, The Journal of Immunology.

[19]  Y. Kurosawa,et al.  Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions. , 1987, Biochemical and biophysical research communications.

[20]  Christopher Garcia.  Faculty Opinions recommendation of Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. , 2002 .

[21]  C. R. Glassman,et al.  A Transmembrane Domain GGxxG Motif in CD4 Contributes to Its Lck-Independent Function but Does Not Mediate CD4 Dimerization , 2015, PloS one.

[22]  A. Barber,et al.  Treatment of multiple myeloma with adoptively transferred chimeric NKG2D receptor-expressing T cells , 2011, Gene Therapy.

[23]  S. Harrison,et al.  Crystal structure of a human CD3-ε/δ dimer in complex with a UCHT1 single-chain antibody fragment , 2004 .

[24]  Marie Malissen,et al.  The proline-rich sequence of CD3ε controls T cell antigen receptor expression on and signaling potency in preselection CD4+CD8+ thymocytes , 2008, Nature Immunology.

[25]  G. Zhu,et al.  B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion , 1999, Nature Medicine.

[26]  Wei Yang,et al.  Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids , 2012, Nature.

[27]  Jia-huai Wang,et al.  Structural basis of assembly of the human T cell receptor–CD3 complex , 2019, Nature.

[28]  T. So,et al.  The TNF-TNFR Family of Co-signal Molecules. , 2019, Advances in experimental medicine and biology.

[29]  L. Hood,et al.  Chimeric immunoglobulin-T cell receptor proteins form functional receptors: Implications for T cell receptor complex formation and activation , 1990, Cell.

[30]  M. Reth.  Antigen receptor tail clue , 1989, Nature.

[31]  P. Love,et al.  ITAM-mediated signaling by the T-cell antigen receptor. , 2010, Cold Spring Harbor perspectives in biology.

[32]  M. Azuma,et al.  The CD28-B7 Family of Co-signaling Molecules. , 2019, Advances in experimental medicine and biology.

[33]  G. Lucchini,et al.  Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR , 2019, Nature Medicine.

[34]  Chenqi Xu,et al.  Ionic CD3−Lck interaction regulates the initiation of T-cell receptor signaling , 2017, Proceedings of the National Academy of Sciences.

[35]  K. Wucherpfennig,et al.  The Assembly of Diverse Immune Receptors Is Focused on a Polar Membrane-Embedded Interaction Site , 2006, PLoS biology.

[36]  M. Call,et al.  Modular Activating Receptors in Innate and Adaptive Immunity. , 2017, Biochemistry.

[37]  Tong Zhang,et al.  Chimeric NK-receptor-bearing T cells mediate antitumor immunotherapy. , 2005, Blood.

[38]  Tomas Mustelin,et al.  Differential and multiple binding of signal transducing molecules to the ITAMs of the TCR‐ζ chain , 1996, Journal of cellular biochemistry.

[39]  T. Beddoe,et al.  Crystal structure of the human T cell receptor CD3εγ heterodimer complexed to the therapeutic mAb OKT3 , 2004 .

[40]  Qing He,et al.  CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia , 2013, Science Translational Medicine.

[41]  Partho Ghosh,et al.  Structure of the complex between human T-cell receptor, viral peptide and HLA-A2 , 1996, Nature.

[42]  Omkar U. Kawalekar,et al.  CAR T cell immunotherapy for human cancer , 2018, Science.

[43]  J. Chou,et al.  The structural basis for intramembrane assembly of an activating immunoreceptor complex , 2010, Nature Immunology.

[44]  I. Pastan,et al.  Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains , 2009, Proceedings of the National Academy of Sciences.

[45]  S. Riddell,et al.  Receptor Affinity and Extracellular Domain Modifications Affect Tumor Recognition by ROR1-Specific Chimeric Antigen Receptor T Cells , 2013, Clinical Cancer Research.

[46]  R. Zamoyska,et al.  Ligand engaged TCR is triggered by Lck not associated with CD8 coreceptor , 2014, Nature Communications.

[47]  B. Evavold,et al.  Two-stage cooperative T cell receptor-peptide major histocompatibility complex-CD8 trimolecular interactions amplify antigen discrimination. , 2011, Immunity.

[48]  L. Varani,et al.  Balance of Anti-CD123 Chimeric Antigen Receptor Binding Affinity and Density for the Targeting of Acute Myeloid Leukemia. , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[49]  Stuart A. Sievers,et al.  Function of Novel Anti-CD19 Chimeric Antigen Receptors with Human Variable Regions Is Affected by Hinge and Transmembrane Domains. , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[50]  Cheng Zhu,et al.  The kinetics of two dimensional TCR and pMHC interactions determine T cell responsiveness , 2010, Nature.

[51]  Jun Wu,et al.  Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells , 1998, Nature.

[52]  C. R. Glassman,et al.  A Mechanical Switch Couples T Cell Receptor Triggering to the Cytoplasmic Juxtamembrane Regions of CD3ζζ. , 2015, Immunity.

[53]  J. Trapani,et al.  Redirecting mouse CTL against colon carcinoma: superior signaling efficacy of single-chain variable domain chimeras containing TCR-zeta vs Fc epsilon RI-gamma. , 2001, Journal of immunology.

[54]  Y. Chen,et al.  Engineering CAR-T Cells for Next-Generation Cancer Therapy. , 2020, Cancer cell.

[55]  E. Reinherz,et al.  Mechanisms contributing to T cell receptor signaling and assembly revealed by the solution structure of an ectodomain fragment of the CD3 epsilon gamma heterodimer. , 2001, Cell.

[56]  K. Sun,et al.  Survival outcomes and efficacy of autologous CD19 chimeric antigen receptor-T cell therapy in the patient with diagnosed hematological malignancies: a systematic review and meta-analysis , 2019, Therapeutics and clinical risk management.

[57]  K. Garcia,et al.  In vitro reconstitution of T cell receptor-mediated segregation of the CD45 phosphatase , 2017, Proceedings of the National Academy of Sciences.

[58]  L. Tuosto,et al.  CD28 costimulatory signals in T lymphocyte activation: Emerging functions beyond a qualitative and quantitative support to TCR signalling. , 2016, Cytokine & growth factor reviews.

[59]  P. Chou,et al.  Cutting Edge: CD3 ITAM Diversity Is Required for Optimal TCR Signaling and Thymocyte Development , 2017, The Journal of Immunology.

[60]  F. Marincola,et al.  Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance , 2015, Journal for ImmunoTherapy of Cancer.

[61]  B. Groner,et al.  A spacer region between the single chain antibody- and the CD3 zeta-chain domain of chimeric T cell receptor components is required for efficient ligand binding and signaling activity. , 1995, Gene therapy.

[62]  Z. Eshhar,et al.  Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[63]  D. Faustman,et al.  Structural principles of tumor necrosis factor superfamily signaling , 2018, Science Signaling.

[64]  C. Mackall,et al.  Clinical lessons learned from the first leg of the CAR T cell journey , 2019, Nature Medicine.

[65]  L. Lanier.  DAP10‐ and DAP12‐associated receptors in innate immunity , 2009, Immunological reviews.

[66]  J. Dörrie,et al.  CARs: Beyond T Cells and T Cell-Derived Signaling Domains , 2020, International journal of molecular sciences.

[67]  Thomas M. Schmitt,et al.  Comparison of T Cell Activities Mediated by Human TCRs and CARs That Use the Same Recognition Domains , 2018, The Journal of Immunology.

[68]  B. Seed,et al.  Cellular immunity to HIV activated by CD4 fused to T cell or Fc receptor polypeptides , 1991, Cell.

[69]  P. Stern,et al.  The Role of Extracellular Spacer Regions in the Optimal Design of Chimeric Immune Receptors: Evaluation of Four Different scFvs and Antigens , 2005, Journal of immunotherapy.

[70]  John R. James,et al.  Tuning ITAM multiplicity on T cell receptors can control potency and selectivity to ligand density , 2018, Science Signaling.

[71]  Alexandria P. Cogdill,et al.  Affinity-Tuned ErbB2 or EGFR Chimeric Antigen Receptor T Cells Exhibit an Increased Therapeutic Index against Tumors in Mice. , 2015, Cancer research.

[72]  Michel Sadelain,et al.  Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ /CD28 receptor , 2002, Nature Biotechnology.

[73]  Robert E. Hawkins,et al.  The Optimal Antigen Response of Chimeric Antigen Receptors Harboring the CD3ζ Transmembrane Domain Is Dependent upon Incorporation of the Receptor into the Endogenous TCR/CD3 Complex , 2010, The Journal of Immunology.

[74]  N. Gascoigne,et al.  Signaling from T cell receptors (TCRs) and chimeric antigen receptors (CARs) on T cells , 2020, Cellular & Molecular Immunology.

[75]  S. Riddell,et al.  The Nonsignaling Extracellular Spacer Domain of Chimeric Antigen Receptors Is Decisive for In Vivo Antitumor Activity , 2014, Cancer Immunology Research.

[76]  S. Endres,et al.  Limitations in the Design of Chimeric Antigen Receptors for Cancer Therapy , 2019, Cells.

[77]  W. Im,et al.  Transmembrane features governing Fc receptor CD16A assembly with CD16A signaling adaptor molecules , 2017, Proceedings of the National Academy of Sciences.

[78]  Yi-Hsin Hsu,et al.  Immunological Synapse Predicts Effectiveness of Chimeric Antigen Receptor Cells , 2018, Molecular therapy : the journal of the American Society of Gene Therapy.

[79]  Michael Loran Dustin,et al.  Spatiotemporal regulation of T cell costimulation by TCR-CD28 microclusters and protein kinase C theta translocation. , 2008, Immunity.

[80]  Pamela A Shaw,et al.  Chimeric antigen receptor T cells for sustained remissions in leukemia. , 2014, The New England journal of medicine.

[81]  Hao Liu,et al.  CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. , 2011, The Journal of clinical investigation.

[82]  A. Lanfranco,et al.  B and T Lymphocyte Attenuator-Mediated Signal Transduction Provides a Potent Inhibitory Signal to Primary Human CD4 T Cells That Can Be Initiated by Multiple Phosphotyrosine Motifs1 , 2006, The Journal of Immunology.

[83]  A. Heimberger,et al.  Tuning Sensitivity of CAR to EGFR Density Limits Recognition of Normal Tissue While Maintaining Potent Antitumor Activity. , 2015, Cancer research.

[84]  Gerhard Wagner,et al.  Structural Features of the αβTCR Mechanotransduction Apparatus That Promote pMHC Discrimination , 2015, Front. Immunol..

[85]  C. Rudd,et al.  The CD4/CD8:p56lck complex in T lymphocytes: a potential mechanism to regulate T-cell growth. , 1989, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[86]  Z. Eshhar,et al.  Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[87]  Simon J Davis,et al.  The kinetic-segregation model: TCR triggering and beyond , 2006, Nature Immunology.

[88]  C. Janeway,et al.  CD4+ T Cells: Specificity and Function , 1988, Immunological reviews.

[89]  H. Einsele,et al.  Inefficient CAR-proximal signaling blunts antigen sensitivity , 2020, Nature Immunology.

[90]  M. Geyer,et al.  CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date. , 2016, Blood.

[91]  Weian Zhao,et al.  CAR-T design: Elements and their synergistic function , 2020, EBioMedicine.

[92]  H. Ji,et al.  Dynamic regulation of CD28 conformation and signaling by charged lipids and ions , 2017, Nature Structural & Molecular Biology.

[93]  W. Im,et al.  A conserved αβ transmembrane interface forms the core of a compact T-cell receptor–CD3 structure within the membrane , 2016, Proceedings of the National Academy of Sciences.

[94]  Michael L Dustin.  The Immunological Synapse , 2014, Cancer Immunology Research.

[95]  K. Roby,et al.  Chimeric NKG2D receptor-bearing T cells as immunotherapy for ovarian cancer. , 2007, Cancer research.

[96]  S. Larson,et al.  Genetically Targeted T Cells Eradicate Systemic Acute Lymphoblastic Leukemia Xenografts , 2007, Clinical Cancer Research.

[97]  K. Wucherpfennig,et al.  Convergence on a distinctive assembly mechanism by unrelated families of activating immune receptors. , 2005, Immunity.

[98]  Todd M. Allen,et al.  Dual CD4-based CAR T cells with distinct costimulatory domains mitigate HIV pathogenesis in vivo , 2020, Nature medicine.

[99]  W. Leonard,et al.  IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. , 2008, Blood.

[100]  C. June,et al.  SHP-1 and SHP-2 Associate with Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary Human T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation1 , 2004, The Journal of Immunology.

[101]  Etienne Gagnon,et al.  Regulation of T Cell Receptor Activation by Dynamic Membrane Binding of the CD3ɛ Cytoplasmic Tyrosine-Based Motif , 2008, Cell.

[102]  Huipin Yuan,et al.  A Rational Strategy for Reducing On-Target Off-Tumor Effects of CD38-Chimeric Antigen Receptors by Affinity Optimization. , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[103]  A. Weiss,et al.  Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases. , 1994, Science.

[104]  J. Orban,et al.  The structural basis of T-cell receptor (TCR) activation: An enduring enigma , 2019, The Journal of Biological Chemistry.

[105]  M. A. Saper,et al.  Structure of the human class I histocompatibility antigen, HLA-A2 , 1987, Nature.

[106]  D. Aivazian,et al.  Phosphorylation of T cell receptor ζ is regulated by a lipid dependent folding transition , 2000, Nature Structural Biology.

[107]  R. Brentjens,et al.  Engineering strategies to overcome the current roadblocks in CAR T cell therapy , 2019, Nature Reviews Clinical Oncology.

[108]  K. D. Hardman,et al.  Single-chain antigen-binding proteins. , 1988, Science.

[109]  L. Walker,et al.  Confusing signals: Recent progress in CTLA-4 biology , 2015, Trends in immunology.

[110]  C. Rudd,et al.  The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[111]  G. Gaud,et al.  Regulatory mechanisms in T cell receptor signalling , 2018, Nature Reviews Immunology.

[112]  Hao Liu,et al.  In Vivo Fate and Activity of Second- versus Third-Generation CD19-Specific CAR-T Cells in B Cell Non-Hodgkin's Lymphomas. , 2018, Molecular therapy : the journal of the American Society of Gene Therapy.

[113]  Reika Watanabe,et al.  Faculty Opinions recommendation of Regulation of T cell receptor activation by dynamic membrane binding of the CD3epsilon cytoplasmic tyrosine-based motif. , 2012 .

[114]  Y. Chien,et al.  CD4 augments the response of a T cell to agonist but not to antagonist ligands. , 1997, Immunity.

[115]  Omer Dushek,et al.  Basic residues in the T-cell receptor ζ cytoplasmic domain mediate membrane association and modulate signaling , 2011, Proceedings of the National Academy of Sciences.

[116]  R. Vale,et al.  Biophysical Mechanism of T Cell Receptor Triggering in a Reconstituted System , 2012, Nature.

[117]  Gerhard Wagner,et al.  Solution structure of the CD3εδ ectodomain and comparison with CD3εγ as a basis for modeling T cell receptor topology and signaling , 2004 .

[118]  S. Agaugué,et al.  Exploiting natural killer group 2D receptors for CAR T-cell therapy. , 2017, Future oncology.

[119]  R. Mariuzza,et al.  Structural and Biophysical Insights into the Role of CD4 and CD8 in T Cell Activation , 2013, Front. Immunol..

[120]  D. Campana,et al.  Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia , 2004, Leukemia.

[121]  P. Linsley,et al.  The role of the CD28 receptor during T cell responses to antigen. , 1993, Annual review of immunology.

[122]  Brian Keith,et al.  Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation. , 2018, JCI insight.

[123]  R. Bruccoleri,et al.  Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in Escherichia coli. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[124]  R. Aebersold,et al.  ZAP-70 binding specificity to T cell receptor tyrosine-based activation motifs: the tandem SH2 domains of ZAP-70 bind distinct tyrosine-based activation motifs with varying affinity , 1995, The Journal of experimental medicine.

[125]  Hai Qi,et al.  Transmembrane domain-mediated Lck association underlies bystander and costimulatory ICOS signaling , 2018, Cellular & Molecular Immunology.

[126]  Mark M Davis,et al.  T cell killing does not require the formation of a stable mature immunological synapse , 2004, Nature Immunology.

[127]  Mark M. Davis,et al.  Direct observation of ligand recognition by T cells , 2002, Nature.

[128]  S. Rosenberg,et al.  Safety and feasibility of anti-CD19 CAR T cells with fully-human binding domains in patients with B-cell lymphoma , 2019, Nature Medicine.

[129]  Mark J. Smyth,et al.  Redirecting Mouse CTL Against Colon Carcinoma: Superior Signaling Efficacy of Single-Chain Variable Domain Chimeras Containing TCR-ζ vs FcεRI-γ1 , 2001, The Journal of Immunology.

[130]  S. Blacklow,et al.  A Zinc Clasp Structure Tethers Lck to T Cell Coreceptors CD4 and CD8 , 2003, Science.

[131]  M. Azuma.  Co-signal Molecules in T-Cell Activation : Historical Overview and Perspective. , 2019, Advances in experimental medicine and biology.

[132]  D. Neuberg,et al.  Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma , 2018, Cancer Immunology Research.

[133]  R. Vale,et al.  Rewired signaling network in T cells expressing the chimeric antigen receptor (CAR) , 2019, bioRxiv.

[134]  J. Lippincott-Schwartz,et al.  The T cell antigen receptor: insights into organelle biology. , 1990, Annual review of cell biology.

[135]  Mark M. Davis,et al.  Deconstructing the form and function of the TCR/CD3 complex. , 2006, Immunity.

[136]  L. K. Ely,et al.  Crystal structure of the human T cell receptor CD3 epsilon gamma heterodimer complexed to the therapeutic mAb OKT3. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[137]  S. Neelapu.  Managing the toxicities of CAR T‐cell therapy , 2019, Hematological oncology.

[138]  I. Screpanti,et al.  A non-conserved amino acid variant regulates differential signalling between human and mouse CD28 , 2018, Nature Communications.

[139]  F. Oliveri,et al.  Specific low-affinity recognition of major histocompatibility complex plus peptide by soluble T-cell receptor , 1992, Nature.

[140]  Mark M. Davis,et al.  The Safety on the TCR Trigger , 2008, Cell.

[141]  J. Berzofsky,et al.  Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function , 2005, The Journal of experimental medicine.

[142]  M. Sadelain,et al.  Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells. , 2015, Cancer cell.

[143]  P. Anton van der Merwe,et al.  The nature of molecular recognition by T cells , 2003, Nature Immunology.

[144]  C. Ware,et al.  B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator , 2005, Nature Immunology.

[145]  S. Weiler,et al.  Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response , 2019, Nature Communications.

[146]  S. Günther,et al.  Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function , 2020, Nature Immunology.

[147]  K. Strebhardt,et al.  GTPase-activating protein Rasal1 associates with ZAP-70 of the TCR and negatively regulates T-cell tumor immunity , 2019, Nature Communications.

[148]  Balbino Alarcón,et al.  Recruitment of Nck by CD3ϵ Reveals a Ligand-Induced Conformational Change Essential for T Cell Receptor Signaling and Synapse Formation , 2002, Cell.

[149]  A. Saitoh,et al.  Development and characterisation of NKp44‐based chimeric antigen receptors that confer T cells with NK cell‐like specificity , 2020, Clinical & translational immunology.

[150]  A. Weiss,et al.  Synergy between the T3/antigen receptor complex and Tp44 in the activation of human T cells. , 1986, Journal of immunology.

[151]  Dongfang Liu,et al.  The Role of Immunological Synapse in Predicting the Efficacy of Chimeric Antigen Receptor (CAR) Immunotherapy , 2020, Cell Communication and Signaling.

[152]  Harvir Singh,et al.  Scalable signaling mediated by T cell antigen receptor–CD3 ITAMs ensures effective negative selection and prevents autoimmunity , 2008, Nature Immunology.

[153]  Arthur Weiss,et al.  The cytoplasmic domain of the T cell receptor ζ chain is sufficient to couple to receptor-associated signal transduction pathways , 1991, Cell.

[154]  Z. Eshhar,et al.  Generation of effector T cells expressing chimeric T cell receptor with antibody type-specificity. , 1989, Transplantation proceedings.

[155]  C. Mackall,et al.  The Emerging Landscape of Immune Cell Therapies , 2020, Cell.

[156]  Mark M Davis,et al.  A single peptide-major histocompatibility complex ligand triggers digital cytokine secretion in CD4(+) T cells. , 2013, Immunity.

[157]  D. Kranz,et al.  T‐cell receptor binding affinities and kinetics: impact on T‐cell activity and specificity , 2009, Immunology.

[158]  P. Cosson,et al.  Role of transmembrane domains in assembly and intracellular transport of the CD8 molecule. , 1993, The Journal of biological chemistry.

[159]  M. Marsh,et al.  Intrinsic Signals in the Unique Domain Target p56lckto the Plasma Membrane Independently of CD4 , 1997, The Journal of cell biology.

[160]  J. Chou,et al.  The structure of the zetazeta transmembrane dimer reveals features essential for its assembly with the T cell receptor. , 2006, Cell.

[161]  D. Margulies,et al.  Structural Basis of the CD8αβ/MHC Class I Interaction: Focused Recognition Orients CD8β to a T Cell Proximal Position12 , 2009, The Journal of Immunology.

[162]  R. Waugh,et al.  T Cell Receptor Signaling Can Directly Enhance the Avidity of CD28 Ligand Binding , 2014, PloS one.

[163]  R. Zinkernagel,et al.  Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system , 1974, Nature.

[164]  M. Davis,et al.  Low affinity interaction of peptide-MHC complexes with T cell receptors. , 1991, Science.

[165]  P. A. van der Merwe,et al.  T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand , 2005, Nature.

[166]  Jim Miller,et al.  Cutting Edge: A Role for Inside-Out Signaling in TCR Regulation of CD28 Ligand Binding , 2011, The Journal of Immunology.

[167]  Haifeng Song,et al.  A safe and potent anti-CD19 CAR T cell therapy , 2019, Nature Medicine.

[168]  N. Okada,et al.  Hinge and Transmembrane Domains of Chimeric Antigen Receptor Regulate Receptor Expression and Signaling Threshold , 2020, Cells.

[169]  W. Schamel,et al.  The TCR is an allosterically regulated macromolecular machinery changing its conformation while working , 2019, Immunological reviews.

[170]  K. Wucherpfennig,et al.  The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[171]  E. Puré,et al.  Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors , 2015, Cancer Immunology Research.

[172]  V. Zarnitsyna,et al.  T cell triggering: insights from 2D kinetics analysis of molecular interactions , 2012, Physical biology.

[173]  M. Minden,et al.  A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects , 2017, Nature Medicine.

[174]  Cheng Zhu,et al.  Accumulation of Dynamic Catch Bonds between TCR and Agonist Peptide-MHC Triggers T Cell Signaling , 2014, Cell.

[175]  Z. Eshhar,et al.  Harnessing Syk family tyrosine kinases as signaling domains for chimeric single chain of the variable domain receptors: optimal design for T cell activation. , 1998, Journal of immunology.

[176]  James McCluskey,et al.  T cell antigen receptor recognition of antigen-presenting molecules. , 2015, Annual review of immunology.

[177]  E. Reinherz,et al.  Solution structure of the CD3epsilondelta ectodomain and comparison with CD3epsilongamma as a basis for modeling T cell receptor topology and signaling. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[178]  E. Reinherz,et al.  Developmentally Regulated Glycosylation of the CD8αβ Coreceptor Stalk Modulates Ligand Binding , 2001, Cell.

[179]  Catherine C L Wong,et al.  Multiple Signaling Roles of CD3ε and Its Application in CAR-T Cell Therapy , 2020, Cell.

[180]  U. Rix,et al.  An immunoproteomic approach to characterize the CAR interactome and signalosome , 2019, Science Signaling.

[181]  Jizhong Lou,et al.  Mechano-regulation of Peptide-MHC Class I Conformations Determines TCR Antigen Recognition. , 2019, Molecular cell.

[182]  P. Wei,et al.  Chimeric Antigen Receptor Designed to Prevent Ubiquitination and Downregulation Showed Durable Antitumor Efficacy. , 2020, Immunity.

[183]  R. Mariuzza,et al.  Crystal structure of a complete ternary complex of T-cell receptor, peptide–MHC, and CD4 , 2012, Proceedings of the National Academy of Sciences.

[184]  E. Reinherz,et al.  The αβ T Cell Receptor Is an Anisotropic Mechanosensor* , 2009, The Journal of Biological Chemistry.

[185]  M. A. Saper,et al.  The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens , 1987, Nature.

[186]  Laura E. Herring,et al.  THEMIS-SHP1 Recruitment by 4-1BB Tunes LCK-Mediated Priming of Chimeric Antigen Receptor-Redirected T Cells. , 2020, Cancer cell.

[187]  A. Lawson,et al.  Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. , 1998, Journal of immunology.

[188]  S. Harrison,et al.  Crystal structure of a human CD3-epsilon/delta dimer in complex with a UCHT1 single-chain antibody fragment. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[189]  A. Sewell,et al.  Peptide-Major Histocompatibility Complex Dimensions Control Proximal Kinase-Phosphatase Balance during T Cell Activation , 2009, The Journal of Biological Chemistry.

[190]  M. Sadelain,et al.  Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency , 2018, Nature Medicine.

[191]  Omer Dushek,et al.  Engineering AvidCARs for combinatorial antigen recognition and reversible control of CAR function , 2020, Nature Communications.

[192]  R. Klausner,et al.  T-cell and basophil activation through the cytoplasmic tail of T-cell-receptor zeta family proteins. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[193]  Michael Loran Dustin,et al.  The immunological synapse , 2002, Arthritis research.