During the last grant cycle, we have characterized a kinetic intermediate in the binding of antigenic peptides to MHC class II molecules. These intermediate complexes are characterized by low affinity and fast association and disassociation rates; they represent peptide-receptive forms, and require a conformational change to occur before converting to stable complexes. The intermediate complexes can be mimicked by variant of flu HA 306-318 peptide (changes to P1-binding residues) and by an HLA-DR1 molecule mutated in the P1 pocket. During the next cycle, we propose to study the biology of these short-lived intermediate complexes, addressing three aims: 1. Characterization of in vitro T cell responses to short-lived complexes, expected to be anergy induction. 2. Identify APCs responsible for anergy induction 3a. Compare peptide repertoires of DO-/-, DM-/- and WT thymic stromal cells 3b. Generate mice expressing a DR1 mutant (DRbG86Y) that participates in short-lived complexes and study thymocyte selection.
| Kim, AeRyon; Hartman, Isamu Z; Poore, Brad et al. (2014) Divergent paths for the selection of immunodominant epitopes from distinct antigenic sources. Nat Commun 5:5369 |
| Sadegh-Nasseri, Scheherazade; Chou, Chih-Ling; Hartman, Isamu Z et al. (2012) How HLA-DM works: recognition of MHC II conformational heterogeneity. Front Biosci (Schol Ed) 4:1325-32 |
| Dalai, Sarat K; Khoruzhenko, Stanislav; Drake, Charles G et al. (2011) Resolution of infection promotes a state of dormancy and long survival of CD4 memory T cells. Immunol Cell Biol 89:870-81 |
| Sadegh-Nasseri, Scheherazade; Natarajan, Sateesh; Chou, Chih-Ling et al. (2010) Conformational heterogeneity of MHC class II induced upon binding to different peptides is a key regulator in antigen presentation and epitope selection. Immunol Res 47:56-64 |
| Hartman, Isamu Z; Kim, AeRyon; Cotter, Robert J et al. (2010) A reductionist cell-free major histocompatibility complex class II antigen processing system identifies immunodominant epitopes. Nat Med 16:1333-40 |
| Sadegh-Nasseri, Scheherazade; Dalai, Sarat K; Korb Ferris, Laura C et al. (2010) Suboptimal engagement of the T-cell receptor by a variety of peptide-MHC ligands triggers T-cell anergy. Immunology 129:1-7 |
| Narayan, Kedar; Su, Katherine W; Chou, Chih-Ling et al. (2009) HLA-DM mediates peptide exchange by interacting transiently and repeatedly with HLA-DR1. Mol Immunol 46:3157-62 |
| Narayan, Kedar; Perkins, Edward M; Murphy, Gavin E et al. (2009) Staphylococcal enterotoxin A induces small clusters of HLA-DR1 on B cells. PLoS One 4:e6188 |
| Dalai, Sarat K; Mirshahidi, Saied; Morrot, Alexandre et al. (2008) Anergy in memory CD4+ T cells is induced by B cells. J Immunol 181:3221-31 |
| Chou, Chih-Ling; Mirshahidi, Saied; Su, Katherine Wailen et al. (2008) Short peptide sequences mimic HLA-DM functions. Mol Immunol 45:1935-43 |
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