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T Cell Receptors Βα Activation of Topologies Maximize Antigen

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T Cell Receptors Βα Activation of Topologies Maximize Antigen Distinctive CD3 Heterodimeric Ectodomain Topologies Maximize Antigen-Triggered Activation of αβ T Cell Receptors This information is current as Sun Taek Kim, Maki Touma, Koh Takeuchi, Zhen-Yu J. of September 27, 2021. Sun, Vibhuti P. Dave, Dietmar J. Kappes, Gerhard Wagner and Ellis L. Reinherz J Immunol 2010; 185:2951-2959; Prepublished online 26 July 2010; doi: 10.4049/jimmunol.1000732 Downloaded from http://www.jimmunol.org/content/185/5/2951 Supplementary http://www.jimmunol.org/content/suppl/2010/07/27/jimmunol.100073 Material 2.DC1 http://www.jimmunol.org/ References This article cites 49 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/185/5/2951.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 27, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Distinctive CD3 Heterodimeric Ectodomain Topologies Maximize Antigen-Triggered Activation of ab T Cell Receptors Sun Taek Kim,*,† Maki Touma,*,† Koh Takeuchi,‡ Zhen-Yu J. Sun,‡ Vibhuti P. Dave,x Dietmar J. Kappes,{ Gerhard Wagner,‡ and Ellis L. Reinherz*,† The ab TCR has recently been suggested to function as an anisotropic mechanosensor during immune surveillance, converting mechanical energy into a biochemical signal upon specific peptide/MHC ligation of the ab clonotype. The heterodimeric CD3«g and CD3«d subunits, each composed of two Ig-like ectodomains, form unique side-to-side hydrophobic interfaces involving their paired G-strands, rigid connectors to their respective transmembrane segments. Those dimers are laterally disposed relative to the ab heterodimer within the TCR complex. In this paper, using structure-guided mutational analysis, we investigate the Downloaded from functional consequences of a striking asymmetry in CD3g and CD3d G-strand geometries impacting ectodomain shape. The uniquely kinked conformation of the CD3g G-strand is crucial for maximizing Ag-triggered TCR activation and surface TCR assembly/expression, offering a geometry to accommodate juxtaposition of CD3g and TCR b ectodomains and foster quaternary change that cannot be replaced by the isologous CD3d subunit’s extracellular region. TCRb and CD3 subunit protein sequence analyses among Gnathostomata species show that the Cb FG loop and CD3g subunit coevolved, consistent with this notion. Further- 2/2 more, restoration of T cell activation and development in CD3g mouse T lineage cells by interspecies replacement can be ratio- http://www.jimmunol.org/ nalized from structural insights on the topology of chimeric mouse/human CD3«d dimers. Most importantly, our findings imply that CD3g and CD3d evolved from a common precursor gene to optimize peptide/MHC-triggered ab TCR activation. The Journal of Immunology, 2010, 185: 2951–2959. cell receptors mediate Ag-specific recognition of peptides These results imply a loose association of individual dimeric extra- bound to MHC (pMHC) molecules via their Fab-like het- cellular TCR segments in the resting state. erodimeric clonotypes. The TCR complex consists of ab, How pMHC ligation of the ab heterodimer on the T cell surface T by guest on September 27, 2021 CD3εg, CD3εd, and CD3zz dimers in a 1:1:1:1 stoichiometry. evokes intracellular signaling via the adjacent CD3 components Whereas the function of the ab clonotype is to bind pMHC, the has been the subject of intense investigation. Previous models associated CD3 subunits mediate signaling through their cytoplas- suggest that TCRs transmit activation signals upon specific pMHC mic (Cyt) tails (1–6). Assembly of the TCR complex is dependent on ligation via clustering, conformational changes, or combining both the transmembrane segment of the individual subunits and their (1, 10–14). Recently we proposed that a common TCR quaternary unique disposition of charged residues in the hydrophobic mem- change rather than conformational alterations of ab clonotypes by brane environment, as detailed elsewhere (7). The ectodomain of pMHCs facilitates signal initiation (15). Given the vast array of ab and the Ig-like CD3εg and CD3εd heterodimers make a limited TCRs and their pMHC ligands, this appears to represent a practi- number of contacts with one another such that, in solution, no inter- cal solution to the T cell immune recognition problem. Clues re- actions are definable by nuclear magnetic resonance (NMR) (8, 9). garding this mechanism were revealed from structural detailing of TCR complex components and by mAb binding studies and anal- ysis of their effects on T cell function. For example, solution struc- *Laboratory of Immunobiology and Department of Medical Oncology, Dana-Farber ε ε Cancer Institute, and †Department of Medicine and ‡Department of Biological Chem- tures of CD3 g and CD3 d heterodimers reveal a unique side-to- istry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; side hydrophobic interface with conjoined b-sheets involving xLymphocyte Development Laboratory, Clinical Research Institute of Montreal, { the G-strands of the two Ig-like ectodomains of each pair (8, 9). Montreal, Quebec, Canada; and Blood Cell Development and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111 The squat and rigid CD3 connecting segments contrast sharply Received for publication March 4, 2010. Accepted for publication June 18, 2010. with the long and flexible a and b connecting peptide linking res- pective constant domains to the transmembrane segments. These This work was supported by National Institutes of Health Grants AI19807 (to E.L.R.), CA74620 (to D.J.K.), AI37581, GM47467, and EB002026 (to G.W.), and Canadian opposing features suggested that the ab heterodimer may move Institutes of Health Research Grant 81145 (to V.P.D.). relative to the CD3εg and CD3εd dimers upon pMHC ligation. By Address correspondence and reprint requests to Dr. Ellis L. Reinherz at the current impeding such movement with H57, an Ab that bridges Cb and address: 77 Avenue Louis Pasteur, HIM 419, Boston, MA 02115. E-mail address: CD3εg (15, 16), pMHC-triggered activation is blocked, consistent [email protected] with this view. The online version of this article contains supplemental material. Agonist anti-CD3 mAbs like 2C11 and 500A2 footprint to the Abbreviations used in this paper: 17A2-A647, 17A2-Alexa Fluor 647; 2C11-F, 2C11- ε FITC; Cyt, cytoplasmic; DN, double negative; FTOC, fetal thymic organ culture; membrane distal CD3 lobe that they approach diagonally, adja- hCD3, human CD3; LN, lymph node; mCD3, murine CD3; MFI, mean fluorescence cent to the lever-like Cb FG loop that facilitates pMHC-triggered intensity; mut, mutant; NMR, nuclear magnetic resonance; pMHC, peptide bound to activation (17, 18). This is the most sensitive TCR triggering di- MHC; tg, transgenic; TM, transmembrane; wt, wild-type. rection (15). In contrast, a nonagonist mAb, 17A2, binds to the Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 cleft between CD3ε and CD3g in a perpendicular mode. 17A2 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1000732 2952 CD3g AND CD3d G-STRAND GEOMETRIES becomes stimulatory only subsequent to application of an external Retroviral transduction and peptide stimulation ∼ tangential (but not normal) force of 50 pN introduced via optical For retroviral transduction, we used the pLZRS-IRES-eGFP vector encod- tweezers. Specific pMHC, but not irrelevant pMHC, activates a ing the enhanced GFP downstream of an internal ribosome entry site (31). T cell upon application of a similar force. During immune sur- The virus supernatant was prepared as described previously (17, 32, 33). veillance, when specific TCR-pMHC ligation occurs, an extracel- For retroviral transduction with CD3gwt and mutant constructs, total LN 2/2 lular mechanical torque may be applied to the TCR prior to “stop cells from N15TCRtgCD3g mice were stimulated with 4 mg/ml con- canavalin A for 2 d, and T cells were purified by removing I-Ab– movement” of the T cell. In this process, the pMHC on the APC positive cells using anti–I-Ab and magnetic beads. N15TCRtgCD3g2/2 functions as a gaff or hook to pull on the ligated TCR on the op- T cells were placed in a 24-well plate at 106 cells/well (volume of posing T cell. Collectively, these findings suggest that the TCR is 300 ml) in complete RPMI 1640 medium, and 300 ml viral supernatant an anisotropic (i.e., directional) mechanosensor. containing 20 mg/ml Lipofectamin (Life Technologies-BRL, Carlsbad, CA) was added to each well and the plate centrifuged at 2000 rpm for We reasoned that detailed analysis of the distinct topology of 1 h at room temperature. Transduced T cells were cultured for 3 d with CD3 heterodimers would provide further insight into the basis of 50 m/ml human rIL-2 until used for the assay. To assess the TCR signaling signal transduction involving the ectodomain components of the of transduced N15TCRtgCD3g2/2 T cells, cells were washed and stimu- TCR mechanosensor. In addition, the rationale for differences in lated with VSV8 peptide-loaded irradiated splenocytes from C57BL/6 mice CD3 subunit requirements for various T lineage populations and or with plate-coated 2C11 (5 mg/ ml) for 4 h in media containing GolgiPlug reagent (BD Pharmingen). Then, cells were stained for surface CD8 and for developmental stages might emerge (19–28).
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