Dr. Sadegh-Nasseri is interested in two general areas of T cell recognition. She investigates the biophysical and biochemical processes that control formation of complexes of antigenic fragments and the MHC Class II, and addresses cellular and molecular events related to T cell tolerance.
CD4+ helper T cells of the immune system recognize peptide fragments of self or foreign antigens that are loaded on MHC-II molecules. Understanding the biochemical and molecular factors that determine which peptides of a given antigen, called “immunodominant epitopes” are selected by the immune system for representing that particular antigen is critically important. Any alterations in the quality and quantity of MHC-II antigen presentation has major implications for the induction of immunologic memory, tolerance, and disease. In fact, it has now become clear that MHC-II antigen processing and presentation plays a major role in the pathophysiology of several autoimmune disorders including MS, infectious diseases such as HIV, and several cancers, including lung cancer.
Our lab has been defining the nature of MHC-II antigen processing and how this affects CD4 T cell recognition and effector function. Among some of our past work, we have shown that having a peptide is essential for the MHC-II structure, determined the number and nature of peptide:MHC contacts to induce activation or hyporesponsiveness (anergy) in CD4T cells, and defined how a protein chaperone HLA-DM allows for selection of high-affinity peptides that can be stably presented to CD4+ T cells. Using the biochemical principles we elucidated from these early studies, we developed a reductionist cell-free MHC-II processing system that is able to identify immunodominant epitopes of a given protein antigen. This system has identified critical epitopes in proteins implicated in autoimmunity as well as protein antigens from influenza, malaria, and HIV-1.
During the past few years, we have been investigating the mechanism of another molecular chaperone, HLA-DO, in MHC-II antigen processing and its role in T cell selection and autoimmunity. Finally, we have recently began a foray into human immunology to investigate the purpose of inducible MHC-II expression on CD4+ T cells, a cell that normally is thought to exclusively respond to, but not present its own, peptides. With these studies, we aim to precisely define the critical molecular determinants of peptide antigen presentation on MHC-II molecules in both the murine and human immune systems. Our goal is ultimately to understand how alterations in peptide presentation and immunodominance can lead to human immune disease, and how to better develop vaccines for infections and cancer that promote T cell recognition of the correct antigenic epitopes.
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Divergent paths for the selection of immunodominant epitopes from distinct antigenic sources. Kim A, Hartman IZ, Poore B, Boronina T, Cole RN, Song N, Ciudad MT, Caspi RR, Jaraquemada D, Sadegh-Nasseri S. Nat Commun. 2014 Nov 21;5:5369. doi: 10.1038/ncomms6369. PMID: 25413013
HLA-DO as the optimizer of epitope selection for MHC class II antigen presentation. Poluektov YO, Kim A, Hartman IZ, Sadegh-Nasseri S. PLoS One. 2013 Aug 8;8(8):e71228. doi: 10.1371/journal.pone.0071228. eCollection 2013. PMID: 23951115
Resolution of infection promotes a state of dormancy and long survival of CD4 memory T cells. Dalai SK, Khoruzhenko S, Drake CG, Jie CC, Sadegh-Nasseri S. Immunol Cell Biol. 2011 Nov;89(8):870-81. doi: 10.1038/icb.2011.2. Epub 2011 Mar 1. PMID: 21358746
A reductionist cell-free major histocompatibility complex class II antigen processing system identifies immunodominant epitopes. 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. Nat Med. 2010 Nov;16(11):1333-40. doi: 10.1038/nm.2248. Epub 2010 Oct 31. PMID: 21037588
Kim AeRyon, Tatiana Boronina, Robert N. Cole, Sadegh-Nasseri S. Linker sequences added to recombinant antigens can skew immunodominant epitope selection during antigen processing. Sci Rep. 2017 Apr 19;7:46418. doi: 10.1038/srep46418. PMID: 28422163
”Method for Identifying and Validating Dominant T Helper Cell Epitopes Using an HLA-DM-Assisted Class II Binding Assay”. Inventor: Sadegh-Nasseri Scheherazade (US)
Patent # US Patent 8,916,340