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NMR: an essential structural tool for integrative studies of T cell development, pMHC ligand recognition and TCR mechanobiology

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Abstract

Early studies of T cell structural biology using X-ray crystallography, surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) focused on a picture of the αβT cell receptor (αβTCR) component domains and their cognate ligands (peptides bound to MHC molecules, i.e. pMHCs) as static interaction partners. Moving forward requires integrating this corpus of data with dynamic technologies such as NMR, molecular dynamics (MD) simulations and real-time single molecule (SM) studies exemplified by optical tweezers (OT). NMR bridges relevant timescales and provides the potential for an all-atom dynamic description of αβTCR components prior to and during interactions with binding partners. SM techniques have opened up vistas in understanding the non-equilibrium nature of T cell signaling through the introduction of force-mediated binding measurements into the paradigm for T cell function. In this regard, bioforces consequent to T-lineage cell motility are now perceived as placing piconewton (pN)-level loads on single receptor-pMHC bonds to impact structural change and αβT-lineage biology, including peptide discrimination, cellular activation, and developmental progression. We discuss herein essential NMR technologies in illuminating the role of ligand binding in the preT cell receptor (preTCR), the αβTCR developmental precursor, and convergence of NMR, SM and MD data in advancing our comprehension of T cell development. More broadly we review the central hypothesis that the αβTCR is a mechanosensor, fostered by breakthrough NMR-based structural insights. Collectively, elucidating dynamic aspects through the integrative use of NMR, SM, and MD shall advance fundamental appreciation of the mechanism of T cell signaling as well as inform translational efforts in αβTCR and chimeric T cell (CAR-T) immunotherapies and T cell vaccinology.

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Acknowledgements

Grant support: AI136301 to MJL; GM047467, AI0037581, and EB002026 to GW; R01AI136960 and R56AI138489 to ELR.

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Authors and Affiliations

  1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA

    Robert J. Mallis, Jia-huai Wang, Gerhard Wagner & Haribabu Arthanari

  2. Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA

    Robert J. Mallis

  3. Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA

    Robert J. Mallis, Kristine N. Brazin, Jonathan S. Duke-Cohan, Jia-huai Wang & Ellis L. Reinherz

  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA

    Kristine N. Brazin, Jonathan S. Duke-Cohan & Ellis L. Reinherz

  5. Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA

    Kristine N. Brazin, Jonathan S. Duke-Cohan & Ellis L. Reinherz

  6. Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA

    Wonmuk Hwang

  7. Department of Materials Science & Engineering, Texas A&M University, College Station, TX, 77843, USA

    Wonmuk Hwang

  8. School of Computational Sciences, Korea Institute for Advanced Study, Seoul, 02455, Republic of Korea

    Wonmuk Hwang

  9. Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA

    Jia-huai Wang

  10. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA

    Haribabu Arthanari

  11. Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, 37235, USA

    Matthew J. Lang

  12. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, 37235, USA

    Matthew J. Lang

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  1. Robert J. Mallis
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Correspondence to Haribabu Arthanari, Matthew J. Lang or Ellis L. Reinherz.

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Mallis, R.J., Brazin, K.N., Duke-Cohan, J.S. et al. NMR: an essential structural tool for integrative studies of T cell development, pMHC ligand recognition and TCR mechanobiology. J Biomol NMR 73, 319–332 (2019). https://doi.org/10.1007/s10858-019-00234-8

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