International Immunology Advance Access originally published online on April 24, 2006
International Immunology 2006 18(6):931-939; doi:10.1093/intimm/dxl029
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Cathepsin L maturation and activity is impaired in macrophages harboring M. avium and M. tuberculosis
1 Department of Microbiology, Ohio State University, 484 West 12th Avenue, Columbus, OH 43210, USA
2 Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA
Correspondence to: P. Bryant; E-mail: bryant.218{at}osu.edu
Mycobacterium tuberculosis-infected macrophages demonstrate diminished capacity to present antigens via class II MHC molecules. Since successful class II MHC-restricted antigen presentation relies on the actions of endocytic proteases, we asked whether the activities of cathepsins (Cat) B, S and L—three major lysosomal cysteine proteases—are modulated in macrophages infected with pathogenic Mycobacterium spp. Infection of murine bone marrow-derived macrophages with either Mycobacterium avium or M. tuberculosis had no obvious effect on Cat B or Cat S activity. In contrast, the activity of Cat L was altered in infected cells. Specifically, whereas the 24-kDa two-chain mature form of active Cat L predominated in uninfected cells, we observed an increase in the steady-state activity of the precursor single-chain (30 kDa) and 25-kDa two-chain forms of the enzyme in cells infected with either M. avium or M. tuberculosis. Pulse-chase analyses revealed that maturation of nascent, single-chain Cat L into the 25-kDa two-chain form was impaired in infected macrophages, and that maturation into the 24-kDa two-chain form did not occur. Consistent with these data, M. avium infection inhibited the IFN
-induced secretion of active two-chain Cat L by macrophages. Viable bacilli were not required to disrupt Cat L maturation, suggesting that a constitutively expressed mycobacterial component was responsible. The absence of the major active form of lysosomal Cat L in M. avium- and M. tuberculosis-infected macrophages may influence the types of T cell epitopes generated in these antigen-presenting cells, and/or the rate of class II MHC peptide loading.
Keywords: antigen-presenting cell, class II MHC, cysteine protease, endocytic pathway
Transmitting editor: H. Ploegh
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