Structural biology has elucidated several general principles for how the ap TCR interacts with peptide- MHC ligands, but several fundamental questions, pertaining to both the recognition and activation of the TCR, remain unanswered. First, we do not yet understand the structural basis of TCR bias for MHC. Is there a recognition code underlying the loosely convergent TCR/pMHC diagonal docking orientations, or """"""""footprints"""""""" so far seen in the different complexes ? A recent TCR/pMHC complex structure we determined suggests there may be limited sets of docking motifs that could be elucidated through structural studies of a series of related complexes. These docking topologies are likely the result of a complex interplay between junctionally-encoded TCR CDR3 interactions with peptide, and the germline- encoded Variable region interactions with the MHC helices. Therefore, we are engineering molecules for structural studies that will isolate the contributions of each of these components. Second, what is the scope of TCR cross-reactivity, and to what extent does TCR CDR conformational flexibility play a role in expanding the T cell repertoire ? Our previous studies suggest that T cell recognition is not broadly promiscuous, and yet there is a prevailing notion that CDR3 induced fit is a mechanism to expand the repertoire of pMHC recognized by the TCR. In order to better understand the role of conformational dynamics in TCR/pMHC interactions, we are determining TCR and pMHC structures, and solution interactions, using Nuclear Magnetic Resonance spectroscopy (NMR). Finally, we currently do not know how TCR and CDS interact in the TCR-CD3 complex. How is recognition of pMHC by the TCR structurally communicated to the associated CD3 subunits for subsequent signaling ? We propose to reconstitute and purify a recombinant form of a full-length, membrane-bound TCR-CD3 complex for biophysical imaging studies. In summary, during the previous term of this award we developed robust methods for expression of TCR, and peptide-MHC that now enable us to carry out a multi-disciplinary analysis of a focused set of TCR/pMHC interactions using x-ray crystallography, NMR, peptide libraries, phage display, and electron microscopy (EM).

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Esch, Thomas R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code
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
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; Mendoza, Juan L; Sethi, Dhruv K et al. (2014) Deconstructing the peptide-MHC specificity of T cell recognition. Cell 157:1073-87
Garcia, K Christopher (2012) Reconciling views on T cell receptor germline bias for MHC. Trends Immunol 33:429-36
Garcia, K Christopher; Gapin, Laurent; Adams, Jarrett J et al. (2012) A closer look at TCR germline recognition. Immunity 36:887-8
Birnbaum, Michael E; Dong, Shen; Garcia, K Christopher (2012) Diversity-oriented approaches for interrogating T-cell receptor repertoire, ligand recognition, and function. Immunol Rev 250:82-101
Garcia, K Christopher (2012) Insights into immune structure, recognition, and signaling. Immunol Rev 250:5-9
Adams, Jarrett J; Narayanan, Samanthi; Liu, Baoyu et al. (2011) T cell receptor signaling is limited by docking geometry to peptide-major histocompatibility complex. Immunity 35:681-93

Showing the most recent 10 out of 28 publications