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 three major efforts underway that are targeted on this objective: 1) dissection of the molecular basis of viral peptide binding and presentation for T-cell recognition by HLA class I molecules; 2) analysis of antigen-presentation pathways for class I- versus class II- restricted antiviral cytotoxic T lymphocyte (CTL) responses; and 3) delineation of the heterogeneity of expressed T-cell receptor (TCR) genes in myelin basic protein (MBP)-reactive T cells obtained from multiple sclerosis (MS) patients. The principle findings are as follow: 1) class I- and class II-restricted T cells can recognize structurally similar, but distinct epitopes of the same viral peptide, and such peptides share a common motif with other peptides that are also recognized by class I- and class II-restricted T cells; 2) common structural features of HLA-A2 molecules can determine the binding and presentation of three diverse viral peptides derived from HTLV-I, human cytomegalovirus (HCMV), and influenza virus; 3) fragments of HLA heavy chains can be successfully expressed in E. coli and utilized together with iodinated beta-2 microglobulin (beta 2m) and peptides to produce a highly specific peptide-binding assay for class I molecules; 4) class II presentation of a cytosolic viral protein can occur in mutant cells that lack HLA-encoded ATP-dependent transporter molecules, whereas class II presentation of a short cytosolic peptide derived from that same viral protein is dependent on such a transporter; and 5) MS patients develop CD4+ CTL responses in vitro to the immunodominant MBP peptide 87-106 that are very heterogeneous at the level of fine specificity, HLA restriction, and TCR V(alpha) and V(beta) usage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002603-09
Application #
3846209
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
1992
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
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
Binz, Anne-Kathrin; Rodriguez, Rene C; Biddison, William E et al. (2003) Thermodynamic and kinetic analysis of a peptide-class I MHC interaction highlights the noncovalent nature and conformational dynamics of the class I heterotrimer. Biochemistry 42:4954-61

Showing the most recent 10 out of 12 publications