Associate Professor
Department of Pathology
School of Medicine

ssadegh@jhmi.edu

664C Ross Building
720 Rutland Avenue
Baltimore, MD 21205

Office: 410-614-4931
Lab: 410-955-4959

A fundamental step in activation of T cells is the interaction of T cell antigen receptors on T cells with short fragments of foreign antigens bound to the proteins of Major Histocompatibility Complex, MHC, expressed on antigen presenting cells.  Our lab is interested in two general areas of T cell recognition: A) We investigate the biophysical and biochemical processes that control formation of complexes of antigenic fragments and the MHC Class II, and B) we address cellular and molecular events related to T cell tolerance.

With respect to A, we have shown that binding of peptides to MHC class II molecules is dynamic and complexa complex, involving multiple steps and conformational intermediates (Sadegh-Nasseri, S and H M McConnell 1989, Sadegh-Nasseri, S, and R N Germain 1991, Sadegh-Nasseri, S, et al 1994, Natarajan, et al 1999). We have learned that differences in conformation induced upon binding of peptides to MHC class II can be recognized by HLA-DM, an accessory molecule helping in capture and selection of antigenic peptides during antigen processing (Sadegh-Nasseri et al, 2008, Narayan, Chou et al 2007, Chou et al 2008, Chou and Sadegh-Nasseri 2000).

We are currently studying factors that contribute to emergence of immunodominance, a phenomenon defined as restricted responsiveness of T cells to a few selected potential epitopes from a complex antigen. Determination of immunodominant epitopes of protein antigens from pathogens and autoimmune diseases is fundamental to the design of potent vaccines and treatment of autoimmune diseases. To achieve this, a unique Cell Free antigen-processing system composed of only purified proteins has been developed. In combination with mass spectrometry, the system can identify physiologically relevant immunodominant epitopes of protein antigens. In addition, the system allows determination of specific roles for molecules that contribute to the selection of immunodominant epitopes during antigen processing.

With respect to B, we have shown that memory T cells become tolerant (unresponsive) to their specific antigen upon recognizing low numbers of peptide/MHC complexes (specific ligand) presented on the antigen presenting cells (Mirshahidi et al 2004, 2001, and Korb et al, 1999). Understanding T cell tolerance is highly desirable for designing strategies to overcome autoimmune diseases. Several current projects seek the mechanism and the physiological significance of T cell anergy, a form of T cell tolerance, in memory T cells.

For a more comprehensive description of our current projects and access to a complete list of publications please visit our lab webpage.

Selected Publications
Narayan, K., K.W. Su, C-L. Chou, S. Khoruzhenko, and S. Sadegh-Nasseri. (2009) HLA-DM mediates peptide exchange by interacting transiently and repeatedly with HLA-DR1. Mol. Immunol. 46:3157-3162.

Narayan, K., E.M. Perkins, G.E. Murphy, S.K. Dalai, M. Edidin, S. Subramaniam, and S. Sadegh-Nasseri (2009) Staphylococcal Enterotoxin A binding forms small clusters of HLA-DR1 on B cells. PLoS One 4:e6188.

Dalai, S.K., S. Mirshahidi, A. Morrot, F. Zavala, and S. Sadegh-Nasseri. (2008) Anergy in Memory CD4+ T Cells is induced by B cells. J. Immunol. 181:3221-3231.

Sadegh-Nasseri, S., M. Chen, K. Narayan, and M. Bouvier. (2008) The convergent roles of tapasin and HLA-DM in antigen presentation. Trends Immunol. 29:141-147.

Chou, C.-L., S. Mirshahidi, K.W. Su, A. Kim, K. Narayan, S. Khoruzhenko, M. Xu, and S. Sadegh-Nasseri. (2008) Short peptide sequences mimic HLA-DM functions. Mol. Immunol. 45:1935?1943.

Narayan, K., C.-L. Chou, A. Kim, I.Z. Hartman, S. Dalai, and S. Sadegh-Nasseri. (2007) HLA-DM targets the hydrogen bond between the histidine at position 81 and peptide to dissociate HLA-DR-peptide complexes. Nat. Immunol. 8:92-100.

Mirshahidi, S., L.C. Korb Ferris and S. Sadegh-Nasseri. (2004) The magnitude of TCR engagement is a critical predictor or T cell anergy or activation. J. Immunol. 172:5346-5355.

Mirshahidi, S., C-T. Huang and S. Sadegh-Nasseri. (2001) Anergy in peripheral memory CD4(+) T cells induced by low avidity engagement of T cell receptor. J. Exp. Med. 194(6):719-731.

Chou, C.-L., and S. Sadegh-Nasseri. (2000) HLA-DM recognizes the flexible conformation of major histocompatibility complex class II. J. Exp. Med. 192:1697-1706.

Korb, L., S. Mirshahidi, K. Ramyar, A. Sadighi Akha, and S. Sadegh-Nasseri. (1999) Induction of T cell anergy by low numbers of agonist ligands. J. Immunol. 162:6401-6409.

Natarajan, S.K., M. Assadi, and 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. 162:4030-4036.

Sadegh-Nasseri, S., L.J. Stern, D.C. Wiley, and R.N. Germain. (1994) Specific low affinity peptide binding precedes stable complex formation and preserves the function of MHC class II molecules. Nature 370:647-650.

Sadegh-Nasseri, S., and R.N. Germain. (1991) A role for peptide in determining MHC class II structure. Nature 353:167-170.

Sadegh-Nasseri, S., and H.M. McConnell. (1989) A kinetic intermediate in the reaction of an antigenic peptide and I-Ek. Nature 337:274-276.