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

Rajeev Mani Nepal^*^,^,1, Bridget Vesosky, Joanne Turner^,^, and Paula Bryant^*^,^,2

^* Department of Microbiology and Divisions of
Infectious Diseases and
Internal Medicine and
Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, USA

² Correspondence at current address: Chemical and Biological Defense Directorate, Defense Threat Reduction Agency, 8725 John J. Kingman Rd., Fort Belvoir, VA, 22060, USA. E-mail: paula.bryant{at}dtra.mil

ABSTRACT

Antigen presentation by class II MHC molecules in the uninfectedhost is a multi-step process involving key functions providedby specific cathepsins (Cat) and the peptide editor DM. Herein,we examined the requirement for each of these components inmice to control a low-dose aerosol infection with Mycobacteriumtuberculosis (MTB). Mice lacking Cat B, -L, or -S were similarto wild-type in their ability to control the growth and disseminationof MTB. In contrast, DM^–/– mice failed to limitMTB growth and showed $~$ 100-fold higher bacterial burden in thelung and spleen (5–6 weeks postinfection) as comparedwith wild-type and Cat-deficient mice. Histopathology revealedimpaired cellular recruitment and altered granuloma formationin the lungs of MTB-infected DM^–/– mice. Moreover,despite impaired thymic selection in Cat L^–/– andDM^–/– mice, MTB-specific CD4⁺ T cells were elicitedonly in the former. The lower numbers of MTB-specific CD4⁺ Tcells available in Cat L^–/– mice as compared withwild-type animals were sufficient to control MTB growth anddissemination. In addition, DM^–/– macrophages infectedwith MTB in vitro were unable to stimulate pathogen-specificT cells. The data indicate that the majority of antigens derivedfrom MTB are loaded onto nascent class II MHC molecules viathe classical DM-dependent pathway.

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