A fundamental step in activation of T cells is the interaction of T cell antigen receptors with short peptides of foreign antigens in complex with proteins of Major Histocompatibility Complex, MHC. Our laboratory is interested in understanding the molecular events that trigger activation of T cells through recognition of defined complexes of peptide-MHC. Thus, we study T cell activation and determine signals that selectively promote activation or tolerance. These investigations have led us to unravel novel strategies for induction of T cell anergy, a form of T cell unresponsiveness. These strategies are explored for treatment of autoimmunity in mouse models.

We have previously shown that binding of peptides to MHC class II molecules is complex and involves kinetic and conformational intermediates. More recently, we have reported that interaction of DM, an accessory molecule involved in antigen presentation, with MHC class II is via recognition of these structural intermediates. Thus, we continue to examine the biological significance of the kinetic and conformational intermediates in folding, peptide loading, and trafficking of MHC class II molecules.

Transgenic mice are used as model systems for studying mechanisms of T cell tolerance in vivo. Recombinant purified T cell receptor and MHC molecules are used for characterization of the interactions of TCR with MHC-peptide complexes. We use recombinant DNA technology for generation of native or altered proteins and express them in insect or E. coli cells. Purification and characterization of the expressed proteins involve different methods in protein chemistry and multiple biophysical techniques including optical biosensors that are used for studying the molecular interactions.

Mirshahidi, Saied, Huang, Ching-Tai, Sadegh-Nasseri, S. (2001) Anergy in Peripheral Memory CD4+ T Cells Induced by Low Avidity Engagement of T Cell Receptor. J. Exp. Med. 17:211-220 [PubMed]

Chou, C.-L., and S. Sadegh-Nasseri. (2000) HLA-DM Recognizes the Flexible Conformation of Major Histocompatibility Complex Class II. J. Exp. Med. 99:11819-11824 [PubMed]

Mirshahidi, S. Ferris, L. C., Sadegh-Nasseri, S. (2000) The magnitude of TCR engagement is a critical predictor of T cell anergy or activation. J. Immunol. 8(2):166-170 [PubMed]

Korb, L., S. Mirshahidi, K. Ramyar, A. Sadighi Akha & S. Sadegh-Nasseri. (1999) Induction of T cell anergy by low numbers of agonist ligands. J. Immunol. 171(2):964-70 [PubMed]

Natarajan, S. K., M. Assadi, & S. Sadegh-Nasseri. (1999) Stable peptide binding to MHC class II molecules is rapid and is determined by a receptive conformation shaped by prior association of low affinity peptides. J. Immunol. 201:291-303 [PubMed]

Sadegh-Nasseri, S., L.J. Stern, D. C. Wiley & RN Germain. (1994) Specific low affinity peptide binding precedes stable complex formation and preserves the function of MHC class II molecules. Nature 202(4):551-60 [PubMed]

Sadegh-Nasseri, S. and R. N. Germain. (1991) A role for peptide in determining MHC class II structure. Nature 17(1):37-42 [PubMed]

Sadegh-Nasseri, S. and H. M. McConnell. (1989) A kinetic intermediate in the reaction of an antigenic peptide and IEk. Nature 18(2):229-41 [PubMed]