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Andrea
Sant
Professor of Microbiology and Immunology Primary Academic Appointment: Center Affiliation: GEBS Cluster Affiliations: |
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| Contact Information | ||
| University of Rochester School of Medicine and Dentistry 601 Elmwood Ave, Box 609 Rochester, New York 14642 |
Phone: (585) 275-9798 E-Mail: andrea_sant@ urmc.rochester.edu |
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- Research Focus
- Immunodominance in CD4 T cell responses
- Research Overview
- The defining feature of the immune system is its ability to distinguish self from non-self, a function mediated by antigen-specific T lymphocytes. T cell receptors can only recognize antigens derived from pathogens or transformed cells if these antigens if the derived peptide fragments of pathogenic proteins combine with Major Histocompatibility Complex (MHC) molecules. The assembly of the antigenic peptide-MHC complex takes place in intracellular compartments, by a series of molecular events collectively referred to as "MHC-restricted antigen presentation". The research in my laboratory centers around the molecular events that regulate MHC class II-restricted antigen presentation and CD4 T cell activation in vivo. Our long term goal is to make connections between the mechanisms involved in peptide acquisition by class II molecules and those aspects of immunology that critically depend on the specific peptides presented by the class II molecule. There are specific areas of research in our laboratory.
- First, our laboratory has a long-standing interest in the mechanisms involved in establishment of immunodominance in CD4 T cell responses. During immune responses pathogens or to protein antigens, T lymphocytes only respond to a limited number of peptide epitopes contained in the immunogens. These peptides are termed "immunodominant". Our experiments seek to understand the elements in vivo that dictate the narrowed selection of specificities in CD4 T cells during protective immune response. Most recently, we have begun to explore the hierarchy of CD4 T cells responses to influenza virus, a human pathogen that poses unique challenges for vaccine design because of its high degree of genetic variability. This research area focuses on understanding the molecular and cellular events that shape and refine the repertoire of CD4 T cells that are specific for influenza virus, using both animal models and analyses of human immune responses. Or research on influenza has the long-term goal of rational vaccine design to develop vaccines that promote heterosubtypic immunity in the CD4 T cell compartment, by developing strategies to focus the CD4 T cells towards the most biologically active and genetically conserved epitopes. Our laboratory is also focused on the intracellular mechanism of peptide loading onto the class II molecule, particularly the role that DM plays in regulating class II-restricted antigen presentation. The MHC-encoded DM molecule is now known to be a critical component of the class II presentation pathway by acting in endosomal compartments of antigens presenting cells. It serves as a catalyst for peptide loading and for editing the peptide repertoire presented by class II molecules on antigen presenting cells, promoting expression of some complexes that can activate CD4 T cells, and extinguishing the expression of other complexes. Our studies are aimed at understanding the molecular basis of such peptide discrimination by DM proteins and the consequences of DM editing in dictating the specificity of CD4 T cell responses. Finally, our laboratory studies the molecular basis for MHC-linked autoimmunity. Genetically-determined susceptibility to autoimmune diseases is frequently associated with the expression of particular MHC class II gene products. Our laboratory is focused on delineating the structural features of MHC molecules that defects in self tolerance and induction of autoimmunity and the role that B cells play as antigen presenting cells during the induction and amplification of autoimmune responses.
- Recent Publications
- Weaver JM, Lazarski CA, Richards KA, Chaves FA, Jenks SA, Menges PR, Sant AJ Immunodominance of CD4 T cells to foreign antigens is peptide intrinsic and independent of molecular context: implications for vaccine design. J Immunol. 2008 Sep 1;181(5):3039-48
- Weaver, J.M., Lararski, C.A., Chaves, F.A., Richards, K.A., Jenks, S.A., Menges, P.R., and Sant, A.J. 2008. Immunodominance of CD4 T cells to foreign antigens is peptide intrinsic and independent of molecular context: Implications for vaccine design. J. Immunol. In press
- Huang S, Gilfillan S, Kim S, Thompson B, Wang X, Sant A.J., Fremont DH, Lantz O, Hansen 2008. TH. MR1 uses an endocytic pathway to activate mucosal-associated invariant T cells. J Exp Med. 205:1201-11.
- Larkin J 3rd, Rankin AL, Picca CC, Riley MP, Jenks SA, Sant AJ, Caton AJ. 2008. CD4+CD25+ regulatory T cell repertoire formation shaped by differential presentation of peptides from a self-antigen. J. Immunol. 180:2149-57.
- Menges, P.R, Jenks, S.A., Bikoff, E.K., Friedman, D., Knowlden, Z. and A. J. Sant. 2007. An MHC class II restriction bias to I-A in CD4 cell responses is altered to I-E in DM-deficient mice. J. Immunol. In press
- Bandyopadhyay, A., Arneson, L. A., Beeson, C. and A.J. Sant 2007. The relative energetic contributions of dominant P1 pocket vs hydrogen bonding interactions to peptide:class II stability: Implications for the mechanism of DM function. Molecular Immunology, In press.
- Gardiner, A., Richards, K.A., Sant, A.J., and L.S. Arneson. 2007. Conformation of MHC class II I-Ag7 is sensitive to the P9 anchor amino acid in bound peptide. International Immunol. 19:1103
- Chaves, F.A. and A. J. Sant. 2007. Measurement of peptide dissociation from MHC Class II molecules. Current Protocols in Immunology, John Wiley and Sons.
- Sant, A.J. Chaves, F., Krafcik, F., Lazarski, C., Menges, P., Richards, K., and J.M. Weaver 2007. Immunodominance in CD4 T cell responses: Implications for immune responses to influenza virus and for vaccine design. Expert. Rev. Vaccines 6:357.
- Richards, K. Chaves, F., Krafcik, F., Topham, D., Lazarski, C and A. J. Sant. 2007. Direct ex vivo analyses reveal an exceptionally broad pattern of immunodominance in the primary HLA-DR1 restricted CD4 T cell response to influenza hemagglutinin. J. Virol. 81:7608.
- Chaves FA, Richards KA, Torelli A, Wedekind J, A.J. Sant, 2006. Peptide-binding motifs for the I-Ad MHC class II molecule: alternate pH-dependent binding behavior. Biochemistry. 2006;45:6426.
- Lazarski CA, Chaves FA, Sant AJ, 2006. The impact of DM on MHC class II-restricted antigen presentation can be altered by manipulation of MHC-peptide kinetic stability. J Exp Med. 203:1319.
- Drake J, and A.J. Sant 2005. The Mechanics of Class II Processing - Establishment of a Peptide-Class II Hierarchy. in Immunodominance - The Choice of the Immune System. Edited by J. Frelinger, Wiley-VCH Press
- Sant, A.J. Chaves, F.C., Jenks, S, Richards, K., Zschoche, P., Weaver, J.M. and C. Lazarski. 2005. The relationship between immunodominance, DM editing and the kinetic stability of MHC class II:peptide complexes. Immunological Reviews. 207:261.
- McFarland, BS, Katz, JF, BS, Sant, AJ, Beeson, CC. 2005. Energetics and Cooperativity of the Hydrogen Bonding and Anchor Interactions That Bind Peptides to MHC Class II Protein. J. Mol. Biol. 1;350:170.
- Chaves, F, Hou, P. and Sant , A. J., 2005. Replacement of the membrane proximal region of I-Ad MHC class II molecule with I-E derived sequences promotes production of an active and stable soluble heterodimer without altering peptide-binding specificity. J. Immunol. Methods. 300:74.
- Lazarski, C, Chavez, F, Jenks, S, Wu, S Richards, K, Weaver, J.M. and A.J. Sant. 2005. The kinetic stability of MHC:class II complexes is a key parameter that dictates immunodominance. Immunity 23:29.
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