• Researcher Profile

    Ellis L. Reinherz, MD

     
    Ellis L. Reinherz, MD
     
    Professor of Medicine, Harvard Medical School

    Office phone: 617-632-3412
    Fax: 617-632-3351
    Email: ellis_reinherz@dfci.harvard.edu
    Website: Cancer Vaccine Center

    Preferred contact method: email
     
     

    Research Department

    Medical Oncology/Hematologic Malignancies

    Area of Research

    Molecular Mechanisms of T Cell Recognition

    Dana-Farber Cancer Institute
    450 Brookline Avenue
    HIM 419
    Boston, MA 02215

    Biography

    Dr. Ellis Reinherz received his MD from Harvard Medical School in 1975. After an internship and residencey at Massachusetts General Hospital from 1975-1977 and a period as a hematology fellow at Brigham and Women's Hospital from 1977-1978, he joined DFCI. In addition to serving as chief of the Laboratory of Immunobiology, he is now director of the newly formed Cancer Vaccine Center. His work has revealed key functional and structural information about T cell receptors (TCRs), the CD3 signaling subunits, and how, with other molecules, TCRs bind to peptide-loaded MHC. His findings have implications for rational vaccine design.

    Research

    Molecular Mechanisms of T Cell Recognition

    Our laboratory continues to work on fundamental processes by which T lymphocytes recognize foreign pathogens including viruses such as smallpox, vaccinia, HIV, and influenza A. We have analyzed the basic function and structure of the T cell receptor (TCR) components: TCRalphabeta heterodimer, CD3epsilongamma and CD3epsilondelta heterodimers, and CD3zetazeta homodimer. In addition, we have derived further detail about CD4 and CD8 coreceptors and their binding to the major histocompatibility complex (MHC) molecules of class II and class I, respectively.

    Recently, we have shown that agonist mAbs footprint to the membrane distal CD3epsilon lobe which they approach diagonally, adjacent to the lever-like Cbeta FG loop that facilitates antigen (pMHC)-triggered activation. In contrast, a non-agonist mAb binds to the cleft between CD3epsilon and CD3gamma in a perpendicular mode and is stimulatory only subsequent to an external tangential but not a normal force (~50 pN) applied via optical tweezers. Specific pMHC but not irrelevant pMHC activates a T cell upon application of a similar force. These findings suggest that the TCR is an anisotropic mechanosensor, converting mechanical energy into a biochemical signal upon specific pMHC ligation during immune surveillance. Activating anti-CD3 mAbs mimic this force via their intrinsic binding mode. A common TCR quaternary change rather than conformational alterations can better facilitate structural signal initiation, given the vast array of TCRs and their specific pMHC ligands.

    Using computational methods, we have also defined the rules concerning the nature of peptides that bind to individual human MHC molecules, including multiple allelic variants, and developed bioinformatic approaches to create computational vaccinology. Further, we have created servers for multiple vaccine development based on prediction of supertypic MHC ligands. We are currently pursuing new mass spectrometry approaches to identify peptides arrayed on individual types of antigen-presenting cells, and defining at a molecular level the extent of T cell recognition of individual immunodominant epitopes as well as non-immunodominant epitopes.

    In the next year, we expect to apply these tools and approaches for characterizing human immune recognition to the area of tumor immunology. In conjunction with the DFCI Cancer Vaccine Center, we will determine the utility of this approach for immunotherapy of cancers.

    Select Publications

    • Meijers R, Lai CC, Yang Y, Liu JH, Zhong W, Wang JH, Reinherz EL. Crystal structures of murine MHC Class I H-2 D(b) and K(b) molecules in complex with CTL epitopes from influenza A virus: implications for TCR repertoire selection and immunodominance. J Mol Biol 2005;345:1099-110.
    • Reche PA, Zhang H, Glutting JP, Reinherz EL. EPIMHC: a curated database of MHC-binding peptides for customized computational vaccinology. Bioinformatics 2005;21:2140-1.
    • Reche PA, Reinherz EL. PEPVAC: a web server for multi-epitope vaccine development based on the prediction of supertypic MHC ligands. Nucleic Acids Res 2005;33:W138-42.
    • Reche PA, Keskin D, Hussey RE, Ancuta P, Gabuzda D, Reinherz EL. Elicitation from virus-naive individuals of cytotoxic T lymphocytes directed against conserved HIV-1 epitopes. Med Immunol. 2006; 5:1
    • Yang H, Kim S-K, Kim M, Reche PA, Morehead TJ, Damon IK, Welsh RM, Reinherz EL. Antiviral chemotherapy facilitating control of poxvirus infections through inhibition of cellular signal transduction. J Clin Invest. 2005; 115; 379-387
    • Touma M, Chang H-C, Sasada T, Clayton LK, Reinherz EL. The TCR Cbeta FG loop regulates alphabeta T cell development by enhancing negative selection. J Immunol. 2006; 176:6812-6823
    • Touma M, Sun ZY, Clayton LK, Marissen WE, Kruisbeek AM, Wagner G, Reinherz EL. Importance of the CD3gamma ectodomain terminal beta-strand and membrane proximal stalk in thymic development and receptor assembly. J Immunol. 2007; 178:3668-3679
    • Brusic V, Marina O, Wu CJ, Reinherz EL. Proteome informatics for cancer research: From molecules to clinic. Proteomics. 2007; 7:976-991
    • Reche PA, Reinherz EL. Definition of MHC supertypes through clustering of MHC peptide-binding repertoires. Methods Mol Biol. 2007; 409:163-173
    • Zhong W, Dixit SB, Mallis RJ, Lugovskoy AA, Beveridge DL, Wagner G, Reinherz EL. CTL recognition of a protective immunodominant influenza A virus nucleoprotein epitope utilizes a highly restricted Vbeta but diverse Valpha repertoire: Functional and structural implications. J Mol Biol. 2007; 372:535-548
    • Sun Z-YJ*, Oh KJ*, Kim M*, Yu J, Brusic V, Song L, Wang J-H, Wagner G, Reinherz EL. HIV-1 broadly neutralizing antibody extracts its epitope from a kinked MPER segment on the viral membrane. Immunity 2008; 28:52-63
    • Wang JH, Mallis RJ, Reinherz EL. Immunodominant-peptide recognition: beta testing TCRalphabeta. Immunity 2008; 28:139-141
    • Lin HH, Ray S, Tongchusak S, Reinherz EL, Brusic V. Evaluation of MHC class I peptide binding prediction servers: Applications for vaccine research. BMC Immunol. 2008; 9:8-21
    • Garcia-Boronat M, Diez-Rivero CM, Reinherz EL, Reche PA. PVS: a web server for protein sequence variability analysis tuned to facilitate conserved epitope discovery. Nucleic Acids Res. 2008; 36:W35-41
    • Reche PA, Reinherz EL. Prediction of peptide-MHC binding using profiles. Methods Mol Biol. 2007; 409:185-200
    • Choi YI, Duke-Cohan J, Ahmed WB, Handley MA, Mann F, Epstein JA, Clayton LK, Reinherz EL. Plexin D1 controls migration of positively-selected thymocytes into the medulla. Immunity, 2008; 29:888-898
    • Lin HH, Zhang GL, Tongchusak S, Reinherz EL, Brusic V. Evaluation of MHC-II peptide binding prediction servers: applications for vaccine research. BMC Bionformatics 2008; 12:S22.
    • Duke-Cohan J, Wollenick K, Witten EA, Seaman MS, Baden LR, Dolin R, Reinherz EL. The heterogeneity of human antibody responses to vaccinia virus revealed through use of focused protein arrays. Vaccine 2009; 27:1154-1165
    • Kim ST, Takeuchi K, Sun Z-YJ, Touma, M, Castro CE, Fahmy A, Lang MJ, Wagner G, Reinherz EL. The alphabeta T cell receptor is an anisotropic mechanosensor. J Biol Chem. 2009; 284:31028-31037

    Investigators

    • Kim, Mikyung, PhD
    • Reinhold, Bruce, PhD
    • Duke-Cohan, Jonathan, PhD
    • Brusic, Vladimir, PhD
    • Anderson, Karen S, MD, PhD
    • Catherine, Ju-Ying Wu, MD
    • Song, Likai, MD, PhD

    Trainees

    • Brazin, Kristine, PhD
    • Liu, Jin-huan, PhD
    • Choi, Young Il, PhD
    • Keskin, Derin, PhD
    • Kim, Sun Taek, PhD
    • Zhou, Bo, PhD
    • Deluca, David, PhD
    • Hainz, Ursula, PhD
    • Wang, Lili, PhD
    • Yoshikawa, Kiyotsugu, PhD
    • Zeng, Wanyong, PhD
    • Zhang, Guanglan, PhD
    • Rajasagi, Mohini, PhD
    • Zhang, Li, PhD
    • Chen, Qiang, PhD
    • Mallis, Robert, PhD
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