Presentation of foreign antigens by MHC class II gene products is a central arm of immunity. The process of MHC class II-dependent antigen presentation involves several discrete steps mediated by proteolytic enzymes: generation of peptides for their subsequent presentation as antigens in peptide complexes with MHC alpha/beta dimers and the stepwise breakdown of the class II-associated molecular chaperone, the invariant chain (Ii). Degradation of Ii promotes loading of MHC class II alpha/beta with newly formed peptides. A single protease, cathepsin S, was recently found to be essential to the process of Ii breakdown and efficient MHC class II peptide loading. These studies are aimed at elucidating the mechanisms by which cathepsin S promotes antigen presentation and at understanding the consequences of inhibition of cathepsin S on MHC class II function. Toward that end, cellular models of antigen presentation in which the activity of cathepsin S, and other cysteine proteases can be manipulated have been developed. Ii resistant to cleavage of cathepsin S will be generated by site-directed mutagenesis and the function of mutant Ii assessed in vitro and in vivo. The importance of cathepsin S in vivo to MHC class II-dependent immune responses, including allergic pulmonary reactions, will be tested by creating a selective, systemic deficiency of cathepsin S with low molecular weight protease inhibitors. And finally, mice with targeted disruption (""""""""knockout"""""""") of the cathepsin S gene are being generated in order to assess the consequences of long-standing cathepsin S deficiency on MHC class II function and to provide a fertile background on which to search for additional proteases important to antigen presentation. These studies should provide new information on the basic events important to MHC class II peptide loading and establish whether there is a clear rationale for therapeutic inhibition of cathepsin S to suppress inflammation in lung diseases promoted by MHC class II-dependent immune reactions such as asthma, hypersensitivity pneumonitis, and transplant rejection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL048261-10
Application #
6490694
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Croxton, Thomas
Project Start
1993-01-01
Project End
2002-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
10
Fiscal Year
2002
Total Cost
$286,892
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Tang, Chi-Hui; Lee, Je-Wook; Galvez, Michael G et al. (2006) Murine cathepsin F deficiency causes neuronal lipofuscinosis and late-onset neurological disease. Mol Cell Biol 26:2309-16
Shi, G-P; Sukhova, G K; Kuzuya, M et al. (2003) Deficiency of the cysteine protease cathepsin S impairs microvessel growth. Circ Res 92:493-500
Riese, R J; Chapman, H A (2000) Cathepsins and compartmentalization in antigen presentation. Curr Opin Immunol 12:107-13
Wolters, P J; Chapman, H A (2000) Importance of lysosomal cysteine proteases in lung disease. Respir Res 1:170-7
Shi, G P; Sukhova, G K; Grubb, A et al. (1999) Cystatin C deficiency in human atherosclerosis and aortic aneurysms. J Clin Invest 104:1191-7
Driessen, C; Bryant, R A; Lennon-Dumenil, A M et al. (1999) Cathepsin S controls the trafficking and maturation of MHC class II molecules in dendritic cells. J Cell Biol 147:775-90
Villadangos, J A; Bryant, R A; Deussing, J et al. (1999) Proteases involved in MHC class II antigen presentation. Immunol Rev 172:109-20
Chapman, H A (1998) Endosomal proteolysis and MHC class II function. Curr Opin Immunol 10:93-102
Riese, R J; Mitchell, R N; Villadangos, J A et al. (1998) Cathepsin S activity regulates antigen presentation and immunity. J Clin Invest 101:2351-63
Sukhova, G K; Shi, G P; Simon, D I et al. (1998) Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J Clin Invest 102:576-83

Showing the most recent 10 out of 12 publications