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Mycobacterium bovis Bacillus Calmette-Guérin Secreting Active Cathepsin S Stimulates Expression of Mature MHC Class II Molecules and Antigen Presentation in Human Macrophages¹

Division of Infectious Diseases, Department of Medicine, University of British Columbia and Vancouver Costal Health Institute, Vancouver, British Columbia, Canada

A successful Th cell response to bacterial infections is induced by mature MHC class II molecules presenting specific Ag peptides on the surface of macrophages. In recent studies, we demonstrated that infection with the conventional vaccine Mycobacterium bovis bacillus Calmette-Guérin (BCG) specifically blocks the surface export of mature class II molecules in human macrophages by a mechanism dependent on inhibition of cathepsin S (Cat S) expression. The present study examined class II expression in macrophages infected with a rBCG strain engineered to express and secrete biologically active human Cat S (rBCG-hcs). Cat S activity was completely restored in cells ingesting rBCG-hcs, which secreted substantial levels of Cat S intracellularly. Thus, infection with rBCG-hcs, but not parental BCG, restored surface expression of mature MHC class II molecules in response to IFN-, presumably as result of MHC class II invariant chain degradation dependent on active Cat S secreted by the bacterium. These events correlated with increased class II-directed presentation of mycobacterial Ag85B to a specific CD4⁺ T cell hybridoma by rBCG-hcs-infected macrophages. Consistent with these findings, rBCG-hcs was found to accelerate the fusion of its phagosome with lysosomes, a process that optimizes Ag processing in infected macrophages. These data demonstrated that intracellular restoration of Cat S activity improves the capacity of BCG-infected macrophages to stimulate CD4⁺ Th cells. Given that Th cells play a major role in protection against tuberculosis, rBCG-hcs would be a valuable tuberculosis vaccine candidate.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by operating grants from the Canadian Institutes of Health Research (CIHR) MOP-67232 and by a grant from the British Columbia Lung Association. Z.H. was supported by scholar awards from the CIHR and the Michael Smith Foundation for Health Research. H.S. and A.T. were supported by the TBVets Charitable Foundation. A.-E.D. was the recipient of a CIHR postdoctoral fellowship.

² H.S. and A.-E.D. contributed equally.

³ Address correspondence and reprint requests to Dr. Zakaria Hmama, Division of Infectious Diseases, University of British Columbia, D452 Heather Pavilion East, 2733 Heather Street, Vancouver, British Columbia, Canada. E-mail address: hmama{at}interchange.ubc.ca

⁴ Abbreviations used in this paper: Mtb, Mycobacterium tuberculosis; TB, tuberculosis; BCG, bacillus Calmette-Guérin; Ii chain, invariant chain; MIIC, MHC class II compartment; Cat S, cathepsin S; OADC, oleic acid, albumin, and dextrose solution; PPD, purified protein derivative; wt, wild type; MDM, monocyte-derived macrophage; MFI, mean fluorescence intensity; TR-DXT, Texas Red-conjugated dextran.