The T cell receptor interaction with peptide-MHC is unique in that each receptor has the capacity to engage and differentially respond to functionally distinct ligands. Understanding the molecular basis for these properties is important not only for mechanistic insight but for clinical translation to antigen-specific immunotherapies. In this proposal we focus on the chemistry of the TCR/pMHC interface, its role in the specificity of both the recognition and triggering phases of TCR signal initiation, and the use of this information to advance immunotherapeutic strategies. In the prior term of this proposal, we developed a technology, yeast peptide-MHC display, which enabled us obtain a deep understanding of the extent of TCR specificity and cross-reactivity. We found that TCRs are highly specific for their cognate antigens despite exhibiting cross-reactivity. This property enabled us to recover the known peptide ligands of TCRs through un-biased screening of pMHC libraries. Now, in Aim #1, this finding has opened up many exciting possibilities: principally to use pMHC display technology to query the specificity of TCRs, and to identify peptide ligands for ?orphan? TCRs in the natural immune system (e.g. Treg) or from pathogenic systems (e.g. cancer, autoimmunity, infectious disease).
In Aim #2 we wish to then then generate high-affinity ?TCR mimic? antibodies, using a novel platform approach, that specifically recognize these newly discovered ligands and enables us to track tissue expression and inducing selective killing of cells expressing these antigens.
In Aim #3, we show that pMHC library technology is also powerful for understanding the relationship between TCR recognition of pMHC and signaling through the capacity of this approach to generate large panels of peptides that can be characterized with respect to signaling and structure. Using this technology, we made the surprising finding that high-affinity, but non-stimulatory pMHC ligands exist in the natural human immune repertoire. We were able to ?isolate? the mechanism of TCR triggering to the formation of ?catch bonds? in the TCR/pMHC interface, which can decouple TCR/pMHC binding strength from signaling.
In Aim #3 of the current proposal we wish to expand on our studies of non-stimulatory TCRs to better understand the molecular mechanisms of triggering at the TCR/pMHC interface, and test a new idea, ?catch bond engineering,? for modifying TCRs to exhibit improved target killing potency in a way that bypasses the dangers of affinity-matured TCRs in adoptive cell therapy. Collectively, this proposal aims to exploit ?first principles? of TCR/pMHC binding chemistry along three different fronts that have direct translational impact.

Public Health Relevance

The molecular principles governing how T cell receptors recognize and signal in response to peptide-MHC antigens have important applications in human health. We wish to exploit T cell receptor/peptide-MHC structure and binding chemistry to develop technologies for TCR ligand identification and TCR signal tuning that will have direct translational impact in cancer immunotherapy, autoimmunity and infectious disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI103867-06
Application #
9851638
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Singleton, Kentner L
Project Start
2013-12-01
Project End
2024-11-30
Budget Start
2019-12-09
Budget End
2020-11-30
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Stanford University
Department
Biophysics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Sibener, Leah V; Fernandes, Ricardo A; Kolawole, Elizabeth M et al. (2018) Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding. Cell 174:672-687.e27
Gee, Marvin H; Han, Arnold; Lofgren, Shane M et al. (2018) Antigen Identification for Orphan T Cell Receptors Expressed on Tumor-Infiltrating Lymphocytes. Cell 172:549-563.e16
Gee, Marvin H; Sibener, Leah V; Birnbaum, Michael E et al. (2018) Stress-testing the relationship between T cell receptor/peptide-MHC affinity and cross-reactivity using peptide velcro. Proc Natl Acad Sci U S A 115:E7369-E7378
Riley, Timothy P; Hellman, Lance M; Gee, Marvin H et al. (2018) T cell receptor cross-reactivity expanded by dramatic peptide-MHC adaptability. Nat Chem Biol 14:934-942
Hilton, Hugo G; McMurtrey, Curtis P; Han, Alex S et al. (2017) The Intergenic Recombinant HLA-B?46:01 Has a Distinctive Peptidome that Includes KIR2DL3 Ligands. Cell Rep 19:1394-1405
Sharon, Eilon; Sibener, Leah V; Battle, Alexis et al. (2016) Genetic variation in MHC proteins is associated with T cell receptor expression biases. Nat Genet 48:995-1002
Adams, Jarrett J; Narayanan, Samanthi; Birnbaum, Michael E et al. (2016) Structural interplay between germline interactions and adaptive recognition determines the bandwidth of TCR-peptide-MHC cross-reactivity. Nat Immunol 17:87-94
Birnbaum, Michael E; Garcia, K Christopher (2015) Self-determination in the T cell repertoire. Immunity 42:8-10
Birnbaum, Michael E; Mendoza, Juan L; Sethi, Dhruv K et al. (2014) Deconstructing the peptide-MHC specificity of T cell recognition. Cell 157:1073-87
Birnbaum, Michael E; Berry, Richard; Hsiao, Yu-Shan et al. (2014) Molecular architecture of the ?? T cell receptor-CD3 complex. Proc Natl Acad Sci U S A 111:17576-81