MHC presentation of peptide has broad importance, as shown by the range of disease conditions influenced by MHC molecules, e.g. infections, tumors, transplantation rejection, and autoimmunity. Cell surface major histocompatibility complex (MHC) class I molecules present tumor- or pathogen-specific peptides to T cells, which respond by lysing malignant or infected cells. Self-MHC class I/peptide complexes are required for the primary selection of the host's repertoire of cytolytic T lymphocytes. In addition, the number of surface MHC class I molecules on target cells influences their recognition by natural killer cells. For all these reasons, cell surface expression of peptide-bearing MHC class I molecules is of immunological importance. Before egress to the cell surface, MHC class I molecules receive peptides within a complex of proteins in the endoplasmic reticulum. In the peptide-loading complex, the protein calreticulin binds to the MHC class I heavy chain, and its presence in the complex is up-regulated by tapasin. Tapasin binds to the MHC class I heavy chain, recruits ERp57 and the transporter associated with antigen processing (TAP), and stabilizes TAP. Although tapasin serves as a critical factor in the control of MHC class I surface expression and peptide presentation, the mechanisms whereby it regulates MHC class I assembly are poorly understood. A more complete understanding of the importance of MHC class I peptide-loading complex interactions involving tapasin would contribute to the creation of strategies to influence peptide presentation for many therapeutic purposes. The objective of this project is to define the mechanisms by which antigen presentation by MHC class I molecules is regulated. Our central hypothesis is that specific interactions of tapasin with other assembly complex proteins regulate the sequence and affinity of MHC class I-binding peptides, the stability of MHC class I/p2m heterodimers prior to final peptide binding, and ultimately cytotoxic T lymphocyte selection and response. We propose these Aims: 1) to determine the role of peptide-loading complex interactions in the stabilization of complete MHC molecules and in the regulation of the MHC class I peptide repertoire, 2) to define the effect of assembly complex interactions on the stability of open MHC class I/p2m heterodimers, and 3) to characterize the impact of peptide-loading complex interactions on T cell recognition, response, and development, using in vitro and in vivo systems. At the completion of this project, it is our expectation that we will have defined contributions of the peptide-loading complex involving tapasin to the regulation of the MHC class I-binding peptide repertoire, MHC class I stabilization, and T cell function.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057428-08
Application #
7227800
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Marino, Pamela
Project Start
1998-05-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
8
Fiscal Year
2007
Total Cost
$222,275
Indirect Cost
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Simone, L C; Tuli, A; Simone, P D et al. (2012) Analysis of major histocompatibility complex class I folding: novel insights into intermediate forms. Tissue Antigens 79:249-62
Peters, Haley L; Tuli, Amit; Wang, Xiaojian et al. (2012) Relevance of amyloid precursor-like protein 2 C-terminal fragments in pancreatic cancer cells. Int J Oncol 41:1464-74
Simone, Laura C; Georgesen, Corey J; Simone, Peter D et al. (2012) Productive association between MHC class I and tapasin requires the tapasin transmembrane/cytosolic region and the tapasin C-terminal Ig-like domain. Mol Immunol 49:628-39
Simone, Laura C; Smith, Brittney L; Solheim, Joyce C (2012) Impact of beta 2-microglobulin on tapasin expression and covalent association. Cell Immunol 279:66-9
Peters, Haley L; Tuli, Amit; Sharma, Mahak et al. (2011) Regulation of major histocompatibility complex class I molecule expression on cancer cells by amyloid precursor-like protein 2. Immunol Res 51:39-44
Williamson, Nicholas A; Reilly, Charles; Tan, Chor-Teck et al. (2011) A novel strategy for the targeted analysis of protein and peptide metabolites. Proteomics 11:183-92
Simone, Laura C; Wang, Xiaojian; Tuli, Amit et al. (2010) Effect of a tapasin mutant on the assembly of the mouse MHC class I molecule H2-K(d). Immunol Cell Biol 88:57-62
Tuli, Amit; Sharma, Mahak; Wang, Xiaojian et al. (2010) Erratum to: Amyloid precursor-like protein 2 association with HLA class I molecules. Cancer Immunol Immunother 59:339
Simone, Laura C; Wang, Xiaojian; Tuli, Amit et al. (2009) Influence of the tapasin C terminus on the assembly of MHC class I allotypes. Immunogenetics 61:43-54
Simone, Laura C; Wang, Xiaojian; Solheim, Joyce C (2009) A transmembrane tail: interaction of tapasin with TAP and the MHC class I molecule. Mol Immunol 46:2147-50

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