T cells of the helper-inducer subset recognize antigen and the class II MHC molecules expressed on accessory cells. For globular protein antigens, the antigen must be processed by the accessory cells prior to T cell recognition. Small peptides can substitute for processed antigen since they can be recognized by T cells when prefixed accessory cells or Ia bearing planar membranes are used to present antigen. We have recently been able to demonstrate that immunogenic peptides bind specifically to Ia-molecules. With a panel of 12 such peptides we have found a correlation between the capacity of an Ia molecule to bind a particular peptide and the capacity of that Ia to serve as a restriction element of the same peptide. Furthermore, we have provided evidence that the complex formed between Ia and peptide is immunologically relevant and that it is this moiety that is recognized by the T cell receptor. We plan to extend our investigations of the role of antigen-Ia interactions in T helper cell responses as follows: 1) To investigate the structural characteristics of peptides that enable them to interact with Ia. 2) To identify the peptide regions within a naturally occurring protein antigen that bind to Ia and to correlate this binding activity to the immunogenicity of these same peptides. 3) To identify and characterize the region(s) within Ia molecules that form the antigen binding site(s) of Ia. 4) To demonstrate and characterize the tri-molecular complex between Ia, antigen, and T cell receptor. 5) To investigate the stoichiometry of Ia-peptide interaction in an attempt to understand why a small fraction of affinity purified Ia appears capable of binding peptide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI018634-09
Application #
3128065
Study Section
Immunobiology Study Section (IMB)
Project Start
1988-08-01
Project End
1993-07-31
Budget Start
1991-08-01
Budget End
1992-07-31
Support Year
9
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Cytel Corporation
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92121
Yang, Wen; Grey, Howard M (2003) Study of the mechanism of TCR antagonism using dual-TCR-expressing T cells. J Immunol 170:4532-8
Kimachi, Kazuhiko; Sugie, Katsuji; Grey, Howard M (2003) Effector T cells have a lower ligand affinity threshold for activation than naive T cells. Int Immunol 15:885-92
Huang, Jianyong; Lo, Pei-Fen; Zal, Tomasz et al. (2002) CD28 plays a critical role in the segregation of PKC theta within the immunologic synapse. Proc Natl Acad Sci U S A 99:9369-73
Wang, Rongfang; Wang-Zhu, Yiran; Grey, Howard (2002) Interactions between double positive thymocytes and high affinity ligands presented by cortical epithelial cells generate double negative thymocytes with T cell regulatory activity. Proc Natl Acad Sci U S A 99:2181-6
Huang, J; Sugie, K; La Face, D M et al. (2000) TCR antagonist peptides induce formation of APC-T cell conjugates and activate a Rac signaling pathway. Eur J Immunol 30:50-8
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Zugel, U; Wang, R; Shih, G et al. (1998) Termination of peripheral tolerance to a T cell epitope by heteroclitic antigen analogues. J Immunol 161:1705-9
Rogers, P R; Grey, H M; Croft, M (1998) Modulation of naive CD4 T cell activation with altered peptide ligands: the nature of the peptide and presentation in the context of costimulation are critical for a sustained response. J Immunol 160:3698-704
Wang, R; Nelson, A; Kimachi, K et al. (1998) The role of peptides in thymic positive selection of class II major histocompatibility complex-restricted T cells. Proc Natl Acad Sci U S A 95:3804-9
Kimachi, K; Croft, M; Grey, H M (1997) The minimal number of antigen-major histocompatibility complex class II complexes required for activation of naive and primed T cells. Eur J Immunol 27:3310-7

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