The immune response within the lung is critically dependent on antigen presentation by the major histocompatibility complex (MHC) class II and CD1 molecules. These antigen presentation pathways are critical effector mechanisms in asthma and host defense against infection. Endosomal cysteine proteases, including cathepsin S, play important roles in trafficking of both MHC class II and CD1d. Antigen presenting cells (APC) devoid of cathepsin activity do not degrade class II-associated invariant chain (Ii) resulting in accumulation of endosomal class II-Ii complexes. Interestingly, APC from cathepsin S-deficient mice also exhibit abnormal endosomal trafficking of CD1ld molecules, resulting in defective selection of NK1.1+T cells. These data implicate an interaction between the MHC class II and CD1d antigen presentation pathways, and suggest that cysteine proteases regulate components of both innate and adaptive immunity. The central hypothesis of the proposed studies is that regulation of cathepsin activity, particularly cathepsins S, L, and F, will control MHC class II- and CD1-restricted antigen presentation, T cell activation, and lung inflammation. To study this hypothesis three specific aims are advanced.
The first aim addresses the hypothesis that different cysteine proteases control Ii proteolysis and MHC class II function in different APC. This hypothesis will be tested by analyzing Ii processing and class II-dependent antigen presentation in cathepsin-deficient APC, derived from a variety of tissues including the lung.
The second aim will focus on examining the molecular basis for class II-CD1d interactions in cathepsin-deficient APC. We will address whether there is a direct class II-CD1d molecular association, or whether these interactions are solely the result of a generalized endosomal trafficking defect.
The third aim i s based on the premise that alteration of cathepsin activity can modulate lung immunity via effects on class II and CD1d function. These studies will use a mouse model of asthma, based on ovalbumin-induced pulmonary inflammation (Th2-type), and a mouse model of mycobacterium tuberculosis pulmonary infection (Th1-type). Together, these studies will probe the basic mechanisms by which cysteine proteases regulate immunity, and will determine whether inhibition of these enzymes can affect MHC class II- and CD1-dependent inflammatory responses within the lung.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI051461-01A1
Application #
6573255
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Sawyer, Richard T
Project Start
2003-02-01
Project End
2008-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
1
Fiscal Year
2003
Total Cost
$374,100
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Chang, Hui-Hsin; Tai, Tzong-Shyuan; Lu, Bing et al. (2012) PTPN22.6, a dominant negative isoform of PTPN22 and potential biomarker of rheumatoid arthritis. PLoS One 7:e33067
Wang, Ying; Baron, Rebecca M; Zhu, Guangli et al. (2006) PU.1 regulates cathepsin S expression in professional APCs. J Immunol 176:275-83