Primary Academic Appointment:
  Dept. of Microbiology and Immunology

Center Affiliation:
  Center for Vaccine Biology and Immunology

GEBS Cluster Affiliations:
 IMV - Immunology, Microbiology, and Virology

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

MHC Class II Restricted Antigen Presentation.

The defining feature of the immune system is its ability to distinguish self from non-self. The major component of the immune system responsible for this self / non-self discrimination is the diverse repertoire of antigen-specific T lymphocytes. One of the major advances in immunology in the past decades is the identification of MHC-restricted recognition of antigen by T lymphocytes. MHC-restricted recognition describes the molecular specificity of the antigen specific receptor on T cells. T cell receptors can only recognize antigens derived from pathogens or transformed cells if these antigens are proteolyzed and if the derived peptide fragments can combine with self proteins termed 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". This process ultimately leads to cell surface deposition of the MHC-peptide complex, where T cell recognition can occur. For a protein to be recognized as "foreign", and thus to elicit a protective immune response, or to be acknowledged as "self", and to induce tolerance, it must be presented by MHC molecules. If this does not occur, the foreign or self protein is essentially invisible to the immune system.

The research in my laboratory centers around the molecular events that regulate MHC class II-restricted antigen presentation. The hypothesis that underlies much of our research is that class II-restricted antigen presentation will be regulated at a number of critical points within the antigen presenting cell (APC) and that structural regions within the MHC class II molecule will influence discrete events along the antigen presentation pathway. Our interest in many aspects of class II biochemistry and function derives from an appreciation of the biological impact of class II regulatory events. 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. Of particular interest to us are T cell receptor repertoire development, immunodominance in protective CD4 T cell responses, and the molecular mechanisms that underlie tissue-specific autoimmunity.

Chaves, F. A, Hou, P, Wu, S, Sant, A. J.. "Replacement of the membrane proximal region of I-A(d) 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(1-2): 74-92. 2005

Lazarski, C. A, Chaves, F. A, Jenks, S. A, Wu, S, Richards, K. A.
Weaver, J. M, Sant, A. J. "The kinetic stability of MHC class II:peptide complexes is a key parameter that dictates immunodominance." Immunity 23(1): 29-40, 2005.

McFarland, B. J, Katz, J. F, Sant, A. J, Beeson, C. "Energetics and cooperativity of the hydrogen bonding and anchor interactions that bind peptides to MHC class II protein." J Mol Biol 350(1): 170-83, 2005.

Arneson LS, Katz JF, Liu M, Sant AJ. Hydrogen bond integrity between MHC class II molecules and bound peptide determines the intracellular fate of MHC class II molecules. J Immunol. 167:6939-46, 2001.

McFarland BJ, Katz JF, Beeson C, Sant AJ. Energetic asymmetry among hydrogen bonds in MHC class II*peptide complexes. Proc Natl Acad Sci U S A. 98:9231-6, 2001.

Nanda NK, Sant AJ. DM determines the cryptic and immunodominant fate of T cell epitopes. J Exp Med. 192:781-8, 2000.

Arneson LS, Peterson M, Sant AJ. The MHC class II molecule I-Ag7 exists in alternate conformations that are peptide dependent. J Immunol. 165:2059-67, 2000.

Sant AJ, Beeson C, McFarland B, Cao J, Ceman S, Bryant PW, Wu S. Individual hydrogen bonds play a critical role in MHC class II: peptide interactions: implications for the dynamic aspects of class II trafficking and DM-mediated peptide exchange. Immunol Rev. 172:239-53, 1999. Review.

McFarland BJ, Sant AJ, Lybrand TP, Beeson C. Ovalbumin(323-339) peptide binds to the major histocompatibility complex class II I-A(d) protein using two functionally distinct registers. Biochemistry 38:16663-70, 1999.

Bryant PW, Roos P, Ploegh HL, Sant AJ. Deviant trafficking of I-Ad mutant molecules is reflected in their peptide binding properties. Eur J Immunol. 29:2729-39, 1999.

McFarland BJ, Beeson C, Sant AJ. Cutting edge: a single, essential hydrogen bond controls the stability of peptide-MHC class II complexes. J Immunol. 163:3567-71, 1999.

Siemasko K, Eisfelder BJ, Stebbins C, Kabak S, Sant AJ, Song W, Clark MR. Ig alpha and Ig beta are required for efficient trafficking to late endosomes and to enhance antigen presentation. J Immunol. 162:6518-25, 1999.