T cell recognition of peptide/MHC complexes is a critical part of virtually all specific immune responses whether appropriate or inappropriate (autoimmune). This type of recognition is mediated by the T cell receptor for antigen, a heterodimeric surface structure resembling immunoglobulin. The focus of this application continues to be the biochemical nature of this interaction and in what ways it is similar and in what ways it is distinct from antibodies binding to their respective antigens. Consequently, one of our first priorities is to follow up our initial characterization of TCR affinity for a single peptide/MHC complex and extend this to include both affinity and kinetic information for a variety of other TCRs and ligands as well. In this way, we will be able to assess the useful range of parameters employed by TCR's and more efficiently compare them with other ligand receptor-pairs. We will also study the kinetic parameters of antagonist/differential signaling peptides/MHC complexes, using both the cytochrome c system and the hemoglobin system. This information may help to choose between the various models proposed for this phenomenon. We have also utilized Circular Dichroism to study TCR binding to peptide/MHC complexes and find evidence suggesting that a conformational change may occur in the TCR. We are interested in defining this phenomenon further and particularly in identifying the residues in the TCR which are responsible for the CD shift as this. would provide clues to the nature of this effect. An altered ability to induce conformational changes in TCRs has also been suggested as a possible mechanism of antagonism and we have begun to survey such complexes.
A third aim i nvolves following up our observation that a chemically cross-linked peptide/MHC dimer of heterodimers can specifically stimulate T cells. If general, this suggests that TCR dimers (induced by MHC dimers) may be sufficient for T cell activation. We will also continue to provide soluble TCRs and MHCs to Dr. Bjorkman's group to aid in crystallization efforts, particularly focused on obtaining a TCR/Ag/MHC co-crystal structure. In addition, we will explore 2D protein crystallization approaches as well. With respect to thymic differentiation we will continue our efforts to identify the natural peptide(s) ligand for a TCR in the thymus, utilizing an antibody raised against MCC/Ek complexes which blocks positive selection of an MCC/Ek specific TCR. Additionally, we have developed an 'MHC tetramer' reagent which can label T cells in an antigen specific manner. This will allow us to track specific T cell populations in the thymus and to address some of the major unresolved issues in thymic differentiation such as the stage at which negative selection is first evident and whether the decision to down regulate CD4 or CD8 is highly regulated or stochastic.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI022511-13
Application #
2457712
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1985-07-01
Project End
2000-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
13
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Davis, Mark M; Tato, Cristina M (2018) Will Systems Biology Deliver Its Promise and Contribute to the Development of New or Improved Vaccines? Seeing the Forest Rather than a Few Trees. Cold Spring Harb Perspect Biol 10:
Davis, Mark M; Tato, Cristina M; Furman, David (2017) Systems immunology: just getting started. Nat Immunol 18:725-732
Glanville, Jacob; Huang, Huang; Nau, Allison et al. (2017) Identifying specificity groups in the T cell receptor repertoire. Nature 547:94-98
de Bourcy, Charles F A; Dekker, Cornelia L; Davis, Mark M et al. (2017) Dynamics of the human antibody repertoire after B cell depletion in systemic sclerosis. Sci Immunol 2:
Rubelt, Florian; Busse, Christian E; Bukhari, Syed Ahmad Chan et al. (2017) Adaptive Immune Receptor Repertoire Community recommendations for sharing immune-repertoire sequencing data. Nat Immunol 18:1274-1278
Ueda, Hironori; Zhou, Jie; Xie, Jianming et al. (2015) Distinct Roles of Cytoskeletal Components in Immunological Synapse Formation and Directed Secretion. J Immunol 195:4117-25
Han, Arnold; Glanville, Jacob; Hansmann, Leo et al. (2015) Corrigendum: Linking T-cell receptor sequence to functional phenotype at the single-cell level. Nat Biotechnol 33:210
Ebert, Peter J R; Jiang, Shan; Xie, Jianming et al. (2009) An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a. Nat Immunol 10:1162-9
Moss, William C; Irvine, Darrell J; Davis, Mark M et al. (2002) Quantifying signaling-induced reorientation of T cell receptors during immunological synapse formation. Proc Natl Acad Sci U S A 99:15024-9
Yang, J; Nagavarapu, U; Relloma, K et al. (2001) Telomerized human microvasculature is functional in vivo. Nat Biotechnol 19:219-24

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