Immunology Faculty Member - Ellis Reinherz, MD

Ellis Reinherz, MD

Dana-Farber Cancer Institute
Department of Medicine
77 Ave. Louis Pasteur, HIM-419
Boston, MA 02115
Tel: 617-632-3412
Fax: 617-632-3351
Email: ellis_reinherz@dfci.harvard.edu
Lab Members: 10 Postdoctoral Fellows, 3 Instructors



Our interests focus on the adaptive immune response with respect to those multiple subunit plasma membrane receptors, namely T cell receptors (TCRs) and preTCRs, that recognize peptides bound to MHC molecules (pMHCs). abTCRs specifically bind to "foreign" peptides, cradled in the groove of MHC molecules and displayed on infected or otherwise perturbed cells including tumor cells through a process that discriminates among potential ligands with exquisite specificity. The paradox that a mere handful of foreign peptides among 100,000 self-peptides is sufficient for cytotoxic T lymphocytes (CTLs) to accurately mount a deadly response or helper T cell to become activated despite apparent weak TCR-pMHC binding at thermal equilibrium was unexplained. Recently, however, it has become clear that TCRs and preTCRs, unlike antibodies, work far from thermal equilibrium, harnessing energy both externally from cell motion during migration and internally from underlying cytoskeletal elements and associated motor proteins. Force-dependent structural transitions and allostery regulate peptide discrimination and pMHC-receptor bond lifetime, allowing for essentially digital mechanosensing to initiate downstream signaling events and immunological synapse formation. Optical tweezers or related technologies to mimic in vivo bioforces can discriminate between T cells whose TCRs manifest outstanding recognition with those which are of poor acuity (several vs. hundreds of pMHC ligands per cell surface, respectively). By developing mechanobiology-dependent T cell readouts in conjunction with ultrasensitive physical detection (i.e. mass spectrometry) rivaling that of high avidity T cells, rational CTL-based vaccine design can follow. The implications for immunotherapeutic vaccines targeting neoantigens, as one example, are significant. Bioforce-dependent measurements can eliminate the micromolar peptide concentrations used to assess T cell recognition via current functional reverse immunology (RI). The latter encourages TCR crossreactivities at high antigen dose and zero force, resulting in false positive detections. In addition, RI is unable to detect stealth epitopes that fail to naturally stimulate T cells due to issues of immunodominance or crosspresentation failure. Notwithstanding, such epitopes may be ideal as targets for CTL vaccine programming.



Last Update: 7/9/2018



Publications

Keskin DB, Reinhold BB, Zhang GL, Ivanov AR, Karger BL, Reinherz EL. Physical detection of influenza A epitopes identifies a stealth subset on human lung epithelium evading natural CD8 immunity. Proc Natl Acad Sci USA. 2015; 112:2151-2156. PMC4343122.

Reinherz, EL. ab TCR-mediated recognition: Relevance to tumor-antigen discovery and cancer immunotherapy. Cancer Immunol Res. 2015; 3:305-312. PMC4391277
Das DK, Mallis RJ, Duke-Cohan JS, Hussey RE, Tetteh PW, Hilton M, Wagner G, Lang MJ, Reinherz EL. Pre-T cell receptors (preTCRs) leverage Vβ CDRs and hydrophobic patch in mechanosensing thymic self-ligands. J Biol Chem., 2016; 291:25292-25305. PMC5207233.

Feng Y, Brazin KN, Kobiyashi E, Mallis RJ, Reinherz EL, Lang MJ. Mechanosensing drives acuity of ab T cell recognition. Proc Natl Acad Sci USA. 2017; 114: E8204-E8213. PMC5625899

Duke-Cohan JS, Ishikawa Y, Yoshizawa A, Choi Y-I, Lee C-N, Acuto O, Kissler S, Reinherz EL. Regulation of thymocyte trafficking by tagap, a GAP-domain protein linked to human autoimmunity. Sci Signaling; 2018; 11:eaan8799. PMID: 29895617



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