The broad, long-term objective of the proposed research is to characterize antigen processing and presentation pathways in dendritic cells (DC), and how these relate to their function in initiating and regulating immune responses. The proposed research is intended to determine the location within DC where peptide and protein-derived antigens are loaded onto class II MHC proteins, and how this is regulated by dendritic cell maturation;to determine the molecular basis for the lack of loading of empty class II MHC proteins present in immature DC;to evaluate possible functional roles for empty class II MHC molecules;and to determine structural characteristics of the peptide-free open conformation of HLA-DR1. These goals will be achieved using cellular and biochemical assays to follow the occupancy and peptide binding activity of class II MHC proteins in antigen presenting cells in different developmental states, and using cellular and immunological assays to follow the functional outcomes of antigen presentation. A novel fluorometric probe of peptide binding has been developed for this purpose. PROJECT NARRATIVE: Antigen presentation by dendritic cells plays a key role in the process by which the immune system recognizes and responds to pathogens. A detailed understanding of the basic cellular processes responsible for antigen presentation will be important to guide therapeutic approaches to regulating inappropriate immune responses as in autoimmunity and allergy, and for efforts to develop new vaccines and to improve existing vaccines against infectious agents and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048833-09
Application #
7761276
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2001-01-29
Project End
2013-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
9
Fiscal Year
2010
Total Cost
$402,188
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pathology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Clement, Cristina C; Becerra, Aniuska; Yin, Liusong et al. (2016) The Dendritic Cell Major Histocompatibility Complex II (MHC II) Peptidome Derives from a Variety of Processing Pathways and Includes Peptides with a Broad Spectrum of HLA-DM Sensitivity. J Biol Chem 291:5576-95
Clement, Cristina C; Moncrieffe, Halima; Lele, Aditi et al. (2016) Autoimmune response to transthyretin in juvenile idiopathic arthritis. JCI Insight 1:
Yin, Liusong; Stern, Lawrence J (2014) Measurement of Peptide Binding to MHC Class II Molecules by Fluorescence Polarization. Curr Protoc Immunol 106:5.10.1-12
Mellins, Elizabeth D; Stern, Lawrence J (2014) HLA-DM and HLA-DO, key regulators of MHC-II processing and presentation. Curr Opin Immunol 26:115-22
Yin, Liusong; Stern, Lawrence J (2014) A novel method to measure HLA-DM-susceptibility of peptides bound to MHC class II molecules based on peptide binding competition assay and differential IC(50) determination. J Immunol Methods 406:21-33
Yin, Liusong; Trenh, Peter; Guce, Abigail et al. (2014) Susceptibility to HLA-DM protein is determined by a dynamic conformation of major histocompatibility complex class II molecule bound with peptide. J Biol Chem 289:23449-64
Yin, Liusong; Stern, Lawrence J (2013) HLA-DM Focuses on Conformational Flexibility Around P1 Pocket to Catalyze Peptide Exchange. Front Immunol 4:336
Guce, Abigail I; Mortimer, Sarah E; Yoon, Taejin et al. (2013) HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism. Nat Struct Mol Biol 20:90-8
Yin, Liusong; Calvo-Calle, J Mauricio; Dominguez-Amorocho, Omar et al. (2012) HLA-DM constrains epitope selection in the human CD4 T cell response to vaccinia virus by favoring the presentation of peptides with longer HLA-DM-mediated half-lives. J Immunol 189:3983-94
Painter, Corrie A; Stern, Lawrence J (2012) Conformational variation in structures of classical and non-classical MHCII proteins and functional implications. Immunol Rev 250:144-57

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