The endosomal cysteine protease, cathepsin S, has a key role in MHC class II (MHCII)-dependent immunity through its role in degradation of the MHCII-associated chaperone, the invariant chain (Ii). But studies of cathepsin S -/- mice also reveal unexpected findings. Cathepsin S deficiency predominantly affects Thl- dependent immunity. IgE responses and Th2-driven pulmonary inflammation, while dependent on cysteine proteases, are normal or increased in cathepsin S -/- mice. Indeed baseline IgE levels and lung mRNA of proinflammatory cytokines in these mice are elevated. Surprisingly, high IgE levels and cytokines are mast cell-dependent. These observations imply additional proteases, and perhaps additional antigen presenting cells (APC), are important to MHCII function and that protease dysregulation can skew, not just block, MHCII-dependent immune responses. Experiments are directed toward understanding how proteases can effect polarization of T and B cell development relevant to lung disease. Mechanisms of peptide loading in cathepsin S-deficient APC will be defined. Mice deficient in the Ii-degrading APC protease cathepsin F have been recently generated and will be used to test the hypothesis that cathepsin F rescues MHC class II peptide display in myeloid APCs, thereby favoring Th2 polarization. Selective protease inhibitors will be used to determine if a set of protease activities in human APC are required for Th2 cytokine production by allergen- stimulated T cells. The mechanisms by which mast cells promote APC-dependent IgE production will be explored by reconstitution of mast cell deficient mice (Wsh) with mast cells cultured from S-/- or cytokine- deficient mice. The overall goal of this application is to understand the molecular basis for protease- dependent polarization of T cell and B cell immune responses and to learn how to exploit this process to ameliorate CD4+ T cell driven disorders such as autoimmunity and asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL048261-15
Application #
7162129
Study Section
Special Emphasis Panel (ZRG1-SSS-3 (03))
Program Officer
Punturieri, Antonello
Project Start
1993-01-01
Project End
2007-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
15
Fiscal Year
2007
Total Cost
$323,212
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
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

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