The major objective of this project is to further define the role of major histocompatibility complex (MHC) antigens in immunocompetent cell interactions and their involvement in the immunogenic association with exogenous antigens. The proposed research is directed toward understanding the nature of T lymphocyte recognition of macrophage-associated antigens and involves a combination of cellular immunological and peptide chemistry approaches. The rational is that by first defining the exogenous antigenic determinants for T cell responsiveness using small synthetic peptide antigens, we may be able to characterize the imunogenic complex presented by macrophages and the antigen recognition process of T cells. Using this approach we will investigate: 1) the critical amino acids of small peptide antigens that are directly recognized by T cells and macrophages; 2) macrophages and T cell structures that specifically bind antigenic determinants of peptide fragments; 3) how macrophages process small peptides to create the immunogenic moiety and the role of macrophage degradation of large proteins to immunogenic fragments; 4) the mechanisms of genetic regulation of immune responsiveness (Ir gene function) to small peptide antigens and the cellular interactions influencing responsiveness; and 5) the relationship between I region-associated (Ia) antigen expression and Ir gene function. The results of these studies should contribute to an understanding of the signals required for lymphocyte activation by elucidating MHC gene product interaction with exogenous antigens and their role in imunocompetent cell interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI019273-07
Application #
3128620
Study Section
Immunobiology Study Section (IMB)
Project Start
1981-12-31
Project End
1991-05-31
Budget Start
1988-06-01
Budget End
1989-05-31
Support Year
7
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Mannie, M D; Nairn, R (1992) Subset-specific co-stimulatory signals are required for IL-2 production but not growth inhibition responses by T cell hybrids specific for myelin basic protein. Cell Immunol 140:219-36
Mannie, M D (1991) A unified model for T cell antigen recognition and thymic selection of the T cell repertoire. J Theor Biol 151:169-92
Mannie, M D; Paterson, P Y; Thomas, D W et al. (1990) Distinct accessory cell requirements define two types of rat T cell hybridomas specific for unique determinants in the encephalitogenic 68-86 region of myelin basic protein. J Immunol 144:440-50
Esch, T R; McKean, D J; Thomas, D W (1990) The role of Ia in the formation of a T cell antigen-recognition complex. J Immunol 145:3979-84
Esch, T R; Thomas, D W (1990) Ia-independent binding of peptide antigen to the T cell receptor. J Immunol 145:3972-8
Shivdasani, R A; Esch, T R; Chen, G H et al. (1990) Monoclonal antibodies define the characteristics and cellular distribution of an Ia-associated protein. Hybridoma 9:17-30
Mannie, M D; Paterson, P Y; U'Prichard, D C et al. (1989) Clonotypic heterogeneity of Lewis rat T cells specific for the encephalitogenic 68-86 region of myelin basic protein. Cell Immunol 122:534-47
Shivdasani, R A; Thomas, D W (1988) Molecular associations of IA antigens after T-B cell interactions. I. Identification of new molecular associations. J Immunol 141:1252-60
Thomas, D W; Solvay, M J; Hadley, G et al. (1988) Functional and biochemical parameters of peptide antigen presentation. Cell Immunol 113:387-403
Kim, K H; Thomas, D W (1988) Two roles for Ia in antigen-specific T cell activation. II. Toward a Velcro model of antigen recognition. J Immunol 140:2500-7

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