DM, but not cathepsin L, is required to control an aerosol infection with Mycobacterium tuberculosis.
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 approximately 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 are loaded onto nascent class II MHC molecules via the classical DM-dependent pathway.
Nepal
Rajeev Mani
RM
Defense Threat Reduction Agency, Fort Belvoir, VA, 22060, USA.
Vesosky
Bridget
B
Turner
Joanne
J
Bryant
Paula
P
D000336:Aerosols; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D056668:Cathepsin L; D002403:Cathepsins / Q000172:deficiency / Q000378:metabolism*; D003433:Crosses, Genetic; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000472:pathogenicity; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D014376:Tuberculosis / Q000276:immunology / Q000635:transmission*
D000336:Aerosols; C585516:DMPK protein, mouse; D000949:Histocompatibility Antigens Class II; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C534278:Ctsl protein, mouse