We wish to analyze the stuctural basis for T cell corecognition of antigen and major histocompatibility complex (MHC) proteins, using purified, soluble forms of the T cell receptor. We will also make antibodies against particular V alpha and V beta domains of soluble T cell receptor proteins to examine possible regulation of V region expression during T cell ontogeny and during the immune response. We will produce soluble T cell receptor protein from chimeric genes containing T cell receptor V region exons and immunoglobulin constant region exons expressed in B cells under the control of immunoglobulin regulatory elements. Chimeric antibodies with T cell receptor binding sites will be purified and used in experiments to determine the specificity and binding constants (association, dissociation and equilibrium) for the T cell receptor to its ligands; peptide antigen and MHC, both individually and together. Comparison of affinities for different antigens and MHC proteins with data on the activation of the original T cell will be used to understand the role of T cell receptor affinity in T cell activation and to determine the relative contribution of antigen and MHC in normal MHC- restricted recognition of antigen. These chimeric proteins will be crystallized for x-ray diffraction determination of their crystal structure. Proteins containing individual alpha or beta chain V domains will be used to produce monoclonal antibodies reactive with these particular V regions, since such reagents have been difficult to produce with conventional immunization. These reagents will be used to examine whether there is a developmental progression in the expression of T cell receptor V regions as occurs with immunoglobulin V regions. Since many of the T cell responses to small antigenic determinants seem to utilize a very limited set of T cell receptor V regions, antibodies against suitable V regions will be used to analyze the T cell repertoire during an immune response and to modify it. Such anti-T cell receptor V region reagents may be useful in diagnosis or treatment of certain diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29GM039476-03
Application #
3466765
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1988-02-01
Project End
1993-01-31
Budget Start
1990-02-01
Budget End
1991-01-31
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037