Accuri C6 Flow Cytometer System
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1207852

Received for publication December 23, 2007.
Revised April 24, 2008.
Accepted for publication June 5, 2008.

Article

DM, but not cathepsin L, is required to control an aerosol infection with Mycobacterium tuberculosis

Rajeev Mani Nepal *{dagger}, Bridget Vesosky {dagger}{ddagger}{sect}, Joanne Turner {dagger}{ddagger}{sect}, and Paula Bryant *{dagger}@

*Department of Microbiology and Divisions of {ddagger}Infectious Diseases and {sect}Internal Medicine and {dagger}Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, USA

@ To whom correspondence should be addressed. E-mail: paula.bryant{at}dtra.mil.


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Abstract

Antigen presentation by class II MHC molecules in the uninfected host is a multi-step process involving key functions provided by specific cathepsins (Cat) and the peptide editor DM. Herein, we examined the requirement for each of these components in mice to control a low-dose aerosol infection with Mycobacterium tuberculosis (MTB). Mice lacking Cat B, -L, or -S were similar to wild-type in their ability to control the growth and dissemination of MTB. In contrast, DM-/- mice failed to limit MTB growth and showed ~100-fold higher bacterial burden in the lung and spleen (5–6 weeks postinfection) as compared with wild-type and Cat-deficient mice. Histopathology revealed impaired cellular recruitment and altered granuloma formation in the lungs of MTB-infected DM-/- mice. Moreover, despite impaired thymic selection in Cat L-/- and DM-/- mice, MTB-specific CD4+ T cells were elicited only in the former. The lower numbers of MTB-specific CD4+ T cells available in Cat L-/- mice as compared with wild-type animals were sufficient to control MTB growth and dissemination. In addition, DM-/- macrophages infected with MTB in vitro were unable to stimulate pathogen-specific T cells. The data indicate that the majority of antigens derived from MTB is loaded onto nascent class II MHC molecules via the classical DM-dependent pathway.

Key Words: class II MHC • antigen presentation • CD4+ T cell