The general objective of this project is to define the mechanisms by which human lymphoid cells interact with antigen-presenting cells in order to produce and regulate immune responses. Over the past year, there have been four major efforts under way that are targeted on this objective: (1) dissection of the molecular basis for peptide binding to class I HLA molecules and presentation for CD8+ T-cell recognition; (2) identification of autoreactive CD8+ T-cell responses to myelin-derived peptides; (3) identification of forms of viral peptide epitopes which can be generated in the endoplasmic reticulum and presented to CD8+ T cells; and (4) identification of peptide~class I HLA complexes recognized by human natural killer cell clones. The principal findings are as follow: (1) isolation and sequencing of endogenous peptides bound to the HLA class I molecules HLA-B14 and HLA-B44 has permitted identification of specific combinations of peptide anchor residues which can be used to successfully predict immunogenic T- cell epitopes within viral peptide sequences that are presented to CD8+ T cells; (2) peptide sequences derived from human myelin basic protein, proteolipid protein, and myelin- associated glycoprotein were identified which could bind to the HLA-A2 molecule and induce auto-reactive CD8+ cytotoxic T- lymphocyte responses in MS patients and normal individuals; (3) a viral peptide molecularly designed as a signal sequence could be cleaved from the carrier protein in the endoplasmic reticulum and bound by HLA-A2 and presented to peptide-specific CD8+ T cells on the cell surface; and (4) we are the first group to unequivocally demonstrate that human natural killer cell clones have cell surface receptors that can specifically recognize class I HLA/peptide complexes in a way which is indistinguishable from CD8+ T cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002603-13
Application #
2579547
Study Section
Special Emphasis Panel (NIB)
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
1996
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Gagnon, Susan J; Borbulevych, Oleg Y; Davis-Harrison, Rebecca L et al. (2006) T cell receptor recognition via cooperative conformational plasticity. J Mol Biol 363:228-43
Gagnon, Susan J; Turner, Richard V; Shiue, Michael G et al. (2006) Extensive T cell receptor cross-reactivity on structurally diverse haptenated peptides presented by HLA-A2. Mol Immunol 43:346-56
Gagnon, Susan J; Borbulevych, Oleg Y; Davis-Harrison, Rebecca L et al. (2005) Unraveling a hotspot for TCR recognition on HLA-A2: evidence against the existence of peptide-independent TCR binding determinants. J Mol Biol 353:556-73
Niland, Brian; Banki, Katalin; Biddison, William E et al. (2005) CD8+ T cell-mediated HLA-A*0201-restricted cytotoxicity to transaldolase peptide 168-176 in patients with multiple sclerosis. J Immunol 175:8365-78
Baxter, Tiffany K; Gagnon, Susan J; Davis-Harrison, Rebecca L et al. (2004) Strategic mutations in the class I major histocompatibility complex HLA-A2 independently affect both peptide binding and T cell receptor recognition. J Biol Chem 279:29175-84
Tomaru, Utano; Yamano, Yoshihisa; Nagai, Masahiro et al. (2003) Detection of virus-specific T cells and CD8+ T-cell epitopes by acquisition of peptide-HLA-GFP complexes: analysis of T-cell phenotype and function in chronic viral infections. Nat Med 9:469-76
Buslepp, Jennifer; Wang, Huanchen; Biddison, William E et al. (2003) A correlation between TCR Valpha docking on MHC and CD8 dependence: implications for T cell selection. Immunity 19:595-606
Gagnon, Susan J; Wang, Zichun; Turner, Richard et al. (2003) MHC recognition by hapten-specific HLA-A2-restricted CD8+ CTL. J Immunol 171:2233-41
Stefanova, Irena; Hemmer, Bernhard; Vergelli, Marco et al. (2003) TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat Immunol 4:248-54
Biddison, William E; Turner, Richard V; Gagnon, Susan J et al. (2003) Tax and M1 peptide/HLA-A2-specific Fabs and T cell receptors recognize nonidentical structural features on peptide/HLA-A2 complexes. J Immunol 171:3064-74

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