Our research projects and interests

 

 


Welcome to the laboratory of

Dr. Scheherazade Sadegh-Nasseri



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Associate Professor, Department of Pathology

School of Medicine, Johns Hopkins University

Johns Hopkins University School of Medicine
Ross Research Building, Rm. 664C
720 Rutland Ave.
Baltimore, Maryland 21205
Office Phone: (410) 614-4931
Fax: (410) 614-3548
Email: ssadegh@jhmi.edu

General lab phone: (410)-614-4959

 

 

 

 

 

 

 

 

 

Scheherazade Sadegh-Nasseri, Ph.D.     

 

We welcome inquiries to join our lab.

To apply, please forward your CV and a statement of interest to Dr. Sadegh-Nasseri by e-mail:

ssadegh@jhmi.edu

 

 

The long-term interests of our lab include:

A) understanding the molecular basis for the generation of ligands for presentation to CD4 T cells, and

B) investigating the parameters that control activation and inactivation of CD4 T cells.

The different projects described below summarize some of the current interests in the lab.

A.

  A fundamental step in the 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, on antigen presenting cells. We have shown that binding of peptides to MHC class II molecules is a complex process and involves 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 1999a, Natarajan, et al 1999b, Sato et al 2000). 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 (Chou and Sadegh-Nasseri 2000). Thus, we continue to explore the biological significance of the kinetic and conformational intermediates in MHC II folding, trafficking, peptide binding, and interaction with the accessory molecules involved in antigen processing and presentation such as HLA-DM and HLA-DO. We utilize different techniques in physical chemistry, biochemistry, nanotechnology, and molecular biology. Few of these techniques are: fluorescence techniques including Fluorometry, Fluorescence microscopy and Forster Resonance Energy Transfer (FRET), Mass Spectrometry, Surface Plasmon Resonance, and Electron Microscopy.

 

  A unique cell free antigen processing system that is composed of only purified protein components has been developed. In combination with mass spectrometry this system can identify physiologically relevant immunodominant epitopes of protein antigens (Hartman). Role for different molecules in antigen processing that contribute to the selection of immunodominant epitopes are being defined.

 

  We study biophysical factors that contribute to the formation of MHC-peptide complexes. These studies extend to interaction of accessory molecules in antigen processing. Currently, the mechanism of interaction of HLA-DM with MHC class II and how its effector function is executed is under study (Narayan et al 2007).

 

  An important related study has focused on defining a role for HLA-DO in antigen processing. Although HLA-DO was defined a decade ago, very little is known about its mechanism of action. We have generated soluble HLA-DO and are investigating interaction with other proteins in antigen processing.

 

B.

 The second main focus in the lab is to understand the engagement of T Cell Receptors by complexes of peptide-MHC II. This interaction is highly complex and results in a spectrum of responses in T cells that range from ignoring the antigenic stimulus to undergoing activation induced cell death. Somewhere in the middle of this range, T cells are positively stimulated to proliferate and make cytokines, or become anergic and refractory to further antigenic stimulations. Our laboratory is interested in understanding the molecular events that are initiated upon recognition of MHC II bound to antigenic peptides by TCR, and the quantitative aspect of helper T cell activation.

 We have established that low avidity engagement of T Cell Receptor by few (1-10) peptide/MHC II complexes per Antigen Presenting Cell (APC) induces anergy (Korb et al., 1999) in T cell clones. Extending these observations to in vivo systems, we found that memory, but not activated or naïve, T cells were anergized when low densities of specific antigens (Mirshahidi et al., 2001) were presented. In another report, we examined differences in the level of activation of TCR-mediated signaling molecules triggered by presentation of stimulatory versus anergy-inducing ligands to T cells (Mirshahidi et al., 2004) . Those experiments provided clear evidence that stimulation of T cells with the ligands of different avidity dictated the nature of T cell responses: a high avidity stimulation induced T cell activation, whereas a low avidity stimulation by the same agonist peptide caused T cell anergy. The above observations highlight the significance of antigen presenting cells (APCs) that encounter T cells and can make them activated or refractory to further stimulations. Because the level of expression of MHC II and other molecules that contribute to T cell-APC membrane interaction can vary on different subpopulations of APCs, it is important to investigate whether certain APCs preferably interact with memory T cells. Induction of tolerance in memory T cells has profound implications for treatment of autoimmune diseases and controlling transplant rejection. It would be of clinical benefit to identify APCs that can present antigen to memory T cells in a tolerogenic fashion

 

  Thus, in one project, we investigate the specific interactions between different APCs with memory CD4 T cells. We examine different antigen presenting cells, and whether specific expression and or architectural assembly of certain molecules on the surface of APCs lead to anergy or activation. Different transgenic mice models are utilized in this project.

 

understanding the molecular basis for the generation of ligands for presentation to CD4 T cells, and

B) investigating the parameters that control activation and inactivation of CD4 T cells.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



      Dr. S. Sadegh-Nasseri's Lab 2011©