The long-term objective of this research is to characterize the physiological role and relevance in the immunological response of an alternative pathway of antigen processing and presentation, known to be active in immature dendritic cells and possibly in central nervous system microglia. Such alternative pathway relay on abundant cell surface expression of empty class II MHC protein and H2-DM for peptide loading and antigen presentation and on secreted dendritic cells proteases for processing of intact proteins into antigenic peptides. Together, these elements comprised an unusual extracellular presentation pathway in which antigen processing and loading occurred entirely outside the cells. The following proposal is aimed to characterize the trafficking pathway of these empty molecules from their synthesis and folding in the ER to their appearance at the cell surface; to understand the developmental regulation of empty class II MHC molecules on immature dendritic cells and their regulation by the cytokine microenvironment; and finally, to define the immunological role of empty class II MHC protein when engaged with T cell receptors expressed on naive, effector and memory subsets of T cell. The proposed research is part of an interactive research project grant. The companion project will focus on the biochemical aspects of antigen processing and peptide loading as part of the characterization of this novel pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048832-05
Application #
6688259
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2003-09-01
Project End
2005-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
5
Fiscal Year
2004
Total Cost
$292,250
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Clement, Cristina C; Aphkhazava, David; Nieves, Edward et al. (2013) Protein expression profiles of human lymph and plasma mapped by 2D-DIGE and 1D SDS-PAGE coupled with nanoLC-ESI-MS/MS bottom-up proteomics. J Proteomics 78:172-87
Cannizzo, Elvira S; Clement, Cristina C; Morozova, Kateryna et al. (2012) Age-related oxidative stress compromises endosomal proteostasis. Cell Rep 2:136-49
Sahu, Ranjit; Kaushik, Susmita; Clement, Cristina C et al. (2011) Microautophagy of cytosolic proteins by late endosomes. Dev Cell 20:131-9
Clement, Cristina C; Cannizzo, Elvira S; Nastke, Maria-Dorothea et al. (2010) An expanded self-antigen peptidome is carried by the human lymph as compared to the plasma. PLoS One 5:e9863
Maitra, Radhashree; Clement, Cristina C; Scharf, Brian et al. (2009) Endosomal damage and TLR2 mediated inflammasome activation by alkane particles in the generation of aseptic osteolysis. Mol Immunol 47:175-84
Chitta, Sriram; Santambrogio, Laura; Stern, Lawrence J (2008) GMCSF in the absence of other cytokines sustains human dendritic cell precursors with T cell regulatory activity and capacity to differentiate into functional dendritic cells. Immunol Lett 116:41-54
Potolicchio, Ilaria; Chitta, Sriram; Xu, Xiaonan et al. (2005) Conformational variation of surface class II MHC proteins during myeloid dendritic cell differentiation accompanies structural changes in lysosomal MIIC. J Immunol 175:4935-47
Santambrogio, Laura; Potolicchio, Ilaria; Fessler, Shawn P et al. (2005) Involvement of caspase-cleaved and intact adaptor protein 1 complex in endosomal remodeling in maturing dendritic cells. Nat Immunol 6:1020-8
Potolicchio, Ilaria; Carven, Gregory J; Xu, Xiaonan et al. (2005) Proteomic analysis of microglia-derived exosomes: metabolic role of the aminopeptidase CD13 in neuropeptide catabolism. J Immunol 175:2237-43
Wong, Siew Heng; Santambrogio, Laura; Strominger, Jack L (2004) Caspases and nitric oxide broadly regulate dendritic cell maturation and surface expression of class II MHC proteins. Proc Natl Acad Sci U S A 101:17783-8

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