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      Optogenetic control shows that kinetic proofreading regulates the activity of the T cell receptor

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          Abstract

          The immune system distinguishes between self and foreign antigens. The kinetic proofreading (KPR) model proposes that T cells discriminate self from foreign ligands by the different ligand binding half-lives to the T cell receptor (TCR). It is challenging to test KPR as the available experimental systems fall short of only altering the binding half-lives and keeping other parameters of the interaction unchanged. We engineered an optogenetic system using the plant photoreceptor phytochrome B (PhyB) as a ligand to selectively control the dynamics of ligand binding to the TCR by light. This opto-ligand-TCR system was combined with the unique property of PhyB to continuously cycle between the binding and non-binding states under red light, with the light intensity determining the cycling rate and thus the binding duration. Mathematical modeling of our experimental datasets showed that indeed the ligand-TCR interaction half-life is the decisive factor for activating downstream TCR signaling, substantiating KPR.

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          Most cited references92

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          Enzymatic assembly of DNA molecules up to several hundred kilobases.

          We describe an isothermal, single-reaction method for assembling multiple overlapping DNA molecules by the concerted action of a 5' exonuclease, a DNA polymerase and a DNA ligase. First we recessed DNA fragments, yielding single-stranded DNA overhangs that specifically annealed, and then covalently joined them. This assembly method can be used to seamlessly construct synthetic and natural genes, genetic pathways and entire genomes, and could be a useful molecular engineering tool.
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            Phenotypic analysis of antigen-specific T lymphocytes.

            Identification and characterization of antigen-specific T lymphocytes during the course of an immune response is tedious and indirect. To address this problem, the peptide-major histocompatability complex (MHC) ligand for a given population of T cells was multimerized to make soluble peptide-MHC tetramers. Tetramers of human lymphocyte antigen A2 that were complexed with two different human immunodeficiency virus (HIV)-derived peptides or with a peptide derived from influenza A matrix protein bound to peptide-specific cytotoxic T cells in vitro and to T cells from the blood of HIV-infected individuals. In general, tetramer binding correlated well with cytotoxicity assays. This approach should be useful in the analysis of T cells specific for infectious agents, tumors, and autoantigens.
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              The Principles of Engineering Immune Cells to Treat Cancer

              Chimeric antigen receptor (CAR) T cells have proven that engineered immune cells can serve as a powerful new class of cancer therapeutics. Clinical experience has helped to define the major challenges that must be met to make engineered T cells a reliable, safe, and effective platform that can be deployed against a broad range of tumors. The emergence of synthetic biology approaches for cellular engineering is providing us with a broadly expanded set of tools for programming immune cells. We discuss how these tools could be used to design the next generation of smart T cell precision therapeutics.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                05 April 2019
                2019
                : 8
                : e42475
                Affiliations
                [1 ]deptSignalling Research Centres BIOSS and CIBSS University of Freiburg FreiburgGermany
                [2 ]deptFaculty of Biology University of Freiburg FreiburgGermany
                [3 ]deptSpemann Graduate School of Biology and Medicine University of Freiburg FreiburgGermany
                [4 ]deptDivision of Theoretical Systems Biology German Cancer Research Center HeidelbergGermany
                [5 ]deptBioQuant Center University of Heidelberg HeidelbergGermany
                [6 ]deptCenter for Chronic Immunodeficiency, Medical Center Freiburg and Faculty of Medicine University of Freiburg FreiburgGermany
                [7 ]deptLaboratory of Systems and Synthetic Biology Wageningen University and Research WageningenNetherlands
                [8 ]deptInstitute of Synthetic Biology and Cluster of Excellence on Plant Sciences University of Düsseldorf DüsseldorfGermany
                Massachusetts Institute of Technology United States
                Massachusetts Institute of Technology United States
                Massachusetts Institute of Technology United States
                Author information
                https://orcid.org/0000-0001-5304-729X
                http://orcid.org/0000-0001-8077-8194
                http://orcid.org/0000-0003-1743-9581
                https://orcid.org/0000-0001-9657-7477
                http://orcid.org/0000-0003-4496-3100
                Article
                42475
                10.7554/eLife.42475
                6488296
                30947807
                d6850d83-7cce-4947-a74e-37e328d31b6a
                © 2019, Yousefi et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 02 October 2018
                : 05 March 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: EXC2189
                Award Recipient :
                Funded by: Deutsche Forschungsgemeinschaft;
                Award ID: GSC-4
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: EXC294
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: EXC81
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: INST 39/899-1 FUGG
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Tools and Resources
                Immunology and Inflammation
                Custom metadata
                Controlling the duration of ligand binding to the T cell receptor by light shows that T cells discriminate stimulatory from non-stimulatory ligands by measuring the dynamics of ligand binding.

                Life sciences
                t cells,ligand-receptor,signaling,dynamics,optogenetics,a. thaliana,human
                Life sciences
                t cells, ligand-receptor, signaling, dynamics, optogenetics, a. thaliana, human

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