Two major interests of our lab include:
I. Understanding the molecular basis for the generation of ligands for presentation to CD4 T cells.
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 such as Dendritic Cells. We have shown that binding of peptides to MHC class II molecules is a complex process and involves multiple kinetic 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 the capture and selection of antigenic peptides during antigen processing (Chou and Sadegh-Nasseri 2000, Narayan et al 2007, Sadegh-Nasseri et al, 2012). We believe that the heterogeneity of peptide/MHC conformation is the basis for interaction with the accessory molecules involved in antigen processing and presentation such as HLA-DM and HLA-DO. To achieve these goals, we utilize different techniques in physical chemistry, biochemistry, nanotechnology, immunology, and molecular biology.
To understand the bases of immunodominance, we have developed a minimalist cell free antigen processing system composed of only purified protein components has been developed in our laboratory. In combination with mass spectrometry this system can identify physiologically relevant immunodominant epitopes of protein antigens (Hartman/Kim et al 2010). Using this unique system, we investigate contributions of different molecules in antigen processing to the selection of immunodominant epitopes.
II. Investigating the parameters that control differentiation and longevity of memory CD4 T cells.
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 tolerized and refractory to further antigenic stimulations.
We have established that low avidity engagement of T Cell Receptor by suboptimal numbers of peptide/MHC II complexes per Antigen Presenting Cell induces a reversible state of unresponsiveness in memory T cells (Korb et al., 1999, Mirshahidi et al., 2001, Mirshahidi et al., 2004, Dalai, et al, 2008, Dalai/Khoruzhenko 2011). These observations highlight the significance of antigen presenting cells (APCs) in regulation of memory T cell activation and dormancy. A major project in the lab is to dissect the genetic control of memory T cell differentiation and longevity over a long period of time in mice and to verify the findings in man.
Dalai SK, Khoruzhenko S, Drake CG, Jie CC, Sadegh-Nasseri S. Resolution of infection promotes a state of dormancy and long survival of CD4 memory T cells. 2011. IMMUNOLOGY AND CELL BIOLOGY, 89:870-81.
Hartman, IZ; Kim, A; Cotter, RJ, Walter K, Dalai SK, Boronina T, Griffith W, Lanar DE, Schwenk R, Krzych U, Cole RN, Sadegh-Nasseri S. A reductionist cell-free major histocompatibility complex class II antigen processing system identifies immunodominant epitopes. 2010. NATURE MEDICINE. 16:1333-40.
Narayan K, Chou CL, Kim A, Hartman IZ, Dalai S, Khoruzhenko S, Sadegh-Nasseri S. HLA-DM targets the hydrogen bond between the histidine at position 81 and peptide to dissociate HLA-DR–peptide complexes. 2007. NATURE IMMUNOLOGY, 8:92-100.
Mirshahidi S, Huang CT, Sadegh-Nasseri S. Anergy in peripheral memory CD4+ T cells induced by low avidity engagement of T cell receptor. 2001. JOURNAL OF EXPERIMENTAL MEDICINE. 194(6):719-31.
Chou C-L, Sadegh-Nasseri S. HLA-DM recognizes the flexible conformation of major histocompatibility complex class II. 2000. JOURNAL OF EXPERIMENTAL MEDICINE,192:1697-706.
Natarajan SK, Assadi M, Sadegh-Nasseri S. 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. 1999. JOURNAL OF IMMUNOLOGY,162: 4030-6