Scheherazade Sadegh-Nasseri, Ph.D.
B.Sc. – Pahlavi University, Shiraz, Iran
Ph.D. – UCLA
Professor, Department of Pathology
Johns Hopkins University School of Medicine
Ross Research Building, Room 664C
720 Rutland Ave., Baltimore, Md. 21205
Keywords: molecular mechanisms in antigen processing and presentation, T cell memory survival, T cell activation, T cell tolerance
A fundamental ste 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 project A, we have shown that binding of peptides to MHC class II molecules is dynamic and 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 the 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 the 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 project 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.
Profile: Publications and Interests