Cathepsins in Antigen Presentation and Lung Immunity

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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 CDld. 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 CD ld molecules, resulting in defective selection of NK1.1 +T cells. These data implicate an interaction between the MHC class II and CD l d 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 ofcathepsin activity, particularly cathepsins S, L, and F, will control MHC class II- and CDl-restricted antigen presentation, T cell activation, and lung inflannnation. 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-CDld interactions in cathepsin-deficient APC. We will address whether there is a direct class II-CD l d molecular association, or whether these interactions are solely the result of a generalized endosomal trafficking defect. The third aim is based on the premise that alteration of cathepsin activity can modulate lung immunity via effects on class II and CDld 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 (Thl-type). Together, these studies will probe the basic mechanisms by which cysteine proteases regulate immunity, and will determine whether inhibition of these enzymes can effect MHC class II- and CDl-dependent inflammatory responses within the lung.