MHC class II restricted antigen processing by Antigen Presenting Cells (APCs) is essential for the development of CD4+ T-cell responses. In this proposal we wish to investigate the involvement in this process of proteins which are resident in the intracellularMIIC class II compartments (MIICs) where the generation of MHC class ll-peptide complexes occurs. The first, defined in the previous grant period, is a gamma interferon-inducible Jysosomal thiolreductase (GILT) which is constitutively expressed in the MIICs of APCs. We hypothesize that GILT is involved in reducing the disulfide bonds within internalized protein antigens which must be broken to allow efficient antigen processing. The second is a subset of the tetraspan family of membrane proteins which resides within MIICs. The prototypical member, also identified in the previous funding period, is CD82. These proteins associate with MHC class II proteins, as well as the related proteins HLA-DM and HLA-DO, which regulate peptide loading within MIICs. We hypothesize that these proteins are involved in the maturation process which segregates class IImolecules from resident proteins with the MHCand therefore regulates the surface expression of MHC class II proteins. We propose to identify substrate proteins which interact with GILT, and to investigate the immunological and physiological functions of GILT using GILT-/- mice. We also propose to investigate the nature of tetraspan interactions with MHC class II molecules and other MIIC proteins, and to determine the role of the tetraspan proteins in MHC class II function at the biochemical level. These studies will unravel novel features of MHC class ll-restricted antigen processing which may prove of clinical importance in immunological diseases, particularly autoimmunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI023081-26
Application #
7758271
Study Section
Special Emphasis Panel (NSS)
Program Officer
Gondre-Lewis, Timothy A
Project Start
1986-01-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
26
Fiscal Year
2010
Total Cost
$385,463
Indirect Cost
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Leonhardt, Ralf M; Abrahimi, Parwiz; Mitchell, Susan M et al. (2014) Three tapasin docking sites in TAP cooperate to facilitate transporter stabilization and heterodimerization. J Immunol 192:2480-94
Leonhardt, Ralf M; Vigneron, Nathalie; Hee, Jia Shee et al. (2013) Critical residues in the PMEL/Pmel17 N-terminus direct the hierarchical assembly of melanosomal fibrils. Mol Biol Cell 24:964-81
Bergman, Cheryl M; Marta, Cecilia B; Maric, Maja et al. (2012) A switch in pathogenic mechanism in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in IFN-?-inducible lysosomal thiol reductase-free mice. J Immunol 188:6001-9
Wagner, Claudia S; Cresswell, Peter (2012) TLR and nucleotide-binding oligomerization domain-like receptor signals differentially regulate exogenous antigen presentation. J Immunol 188:686-93
Hastings, Karen Taraszka; Cresswell, Peter (2011) Disulfide reduction in the endocytic pathway: immunological functions of gamma-interferon-inducible lysosomal thiol reductase. Antioxid Redox Signal 15:657-68
Seo, Jun-Young; Yaneva, Rakina; Cresswell, Peter (2011) Viperin: a multifunctional, interferon-inducible protein that regulates virus replication. Cell Host Microbe 10:534-9
Leonhardt, Ralf M; Vigneron, Nathalie; Rahner, Christoph et al. (2011) Proprotein convertases process Pmel17 during secretion. J Biol Chem 286:9321-37
Roche, Paul A; Cresswell, Peter (2011) Proteolysis of the class II-associated invariant chain generates a peptide binding site in intracellular HLA-DR molecules. Proc. Natl. Acad. Sci. USA. 1991. 88: 3150-3154. J Immunol 187:1076-80
Rausch, Matthew P; Irvine, Kari R; Antony, Paul A et al. (2010) GILT accelerates autoimmunity to the melanoma antigen tyrosinase-related protein 1. J Immunol 185:2828-35
Leonhardt, Ralf M; Vigneron, Nathalie; Rahner, Christoph et al. (2010) Endoplasmic reticulum export, subcellular distribution, and fibril formation by Pmel17 require an intact N-terminal domain junction. J Biol Chem 285:16166-83

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