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Journal of Biomolecular NMR

, Volume 73, Issue 6–7, pp 319–332 | Cite as

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

  • Robert J. Mallis
  • Kristine N. Brazin
  • Jonathan S. Duke-Cohan
  • Wonmuk Hwang
  • Jia-huai Wang
  • Gerhard Wagner
  • Haribabu ArthanariEmail author
  • Matthew J. LangEmail author
  • Ellis L. ReinherzEmail author
Perspective
  • 426 Downloads

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.

Keywords

Integrative structural biology Nuclear magnetic resonance spectroscopy (NMR) Optical tweezers Single molecule Molecular dynamics (MD) T cell receptor (TCR) PreT cell receptor (preTCR) 

Notes

Acknowledgements

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

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Biological Chemistry and Molecular PharmacologyHarvard Medical SchoolBostonUSA
  2. 2.Department of DermatologyHarvard Medical SchoolBostonUSA
  3. 3.Laboratory of ImmunobiologyDana-Farber Cancer InstituteBostonUSA
  4. 4.Department of Medical OncologyDana-Farber Cancer InstituteBostonUSA
  5. 5.Department of MedicineHarvard Medical SchoolBostonUSA
  6. 6.Department of Biomedical EngineeringTexas A&M UniversityCollege StationUSA
  7. 7.Department of Materials Science & EngineeringTexas A&M UniversityCollege StationUSA
  8. 8.School of Computational SciencesKorea Institute for Advanced StudySeoulRepublic of Korea
  9. 9.Department of PediatricsHarvard Medical SchoolBostonUSA
  10. 10.Department of Cancer BiologyDana-Farber Cancer InstituteBostonUSA
  11. 11.Department of Chemical and Biomolecular EngineeringVanderbilt UniversityNashvilleUSA
  12. 12.Department of Molecular Physiology and BiophysicsVanderbilt University School of MedicineNashvilleUSA

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