Bacterial protein secretion is required for priming of CD8+ T cells specific for the Mycobacterium tuberculosis antigen CFP10.
Mycobacterium tuberculosis infection elicits antigen-specific CD8(+) T cells that are required to control disease. It is unknown how the major histocompatibility complex class I (MHC-I) pathway samples mycobacterial antigens. CFP10 and ESAT6 are important virulence factors secreted by M. tuberculosis, and they are immunodominant targets of the human and murine T-cell response. Here, we test the hypothesis that CFP10 secretion by M. tuberculosis is required for the priming of CD8(+) T cells in vivo. Our results reveal an explicit dependence upon the bacterial secretion of the CFP10 antigen for the induction of antigen-specific CD8(+) T cells in vivo. By using well-defined M. tuberculosis mutants and carefully controlling for virulence, we show that ESX-1 function is required for the priming of CD8(+) T cells specific for CFP10. CD4(+) and CD8(+) T-cell responses to mycobacterial antigens secreted independently of ESX-1 were unaffected, suggesting that ESX-1-dependent phagosomal escape is not required for CD8(+) T-cell priming during infection. We propose that the overrepresentation of secreted proteins as dominant targets of the CD8(+) T-cell response during M. tuberculosis infection is a consequence of their preferential sampling by the MHC-I pathway. The implications of these findings should be considered in all models of antigen presentation during M. tuberculosis infection and in vaccine development.
Woodworth
Joshua S
JS
Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Fortune
Sarah M
SM
Behar
Samuel M
SM
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology* / Q000378:metabolism; D001426:Bacterial Proteins / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D018398:Homeodomain Proteins / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000502:physiology; D014157:Transcription Factors / Q000172:deficiency / Q000502:physiology
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C117940:CFP-10 protein, Mycobacterium tuberculosis; C093276:ESAT-6 protein, Mycobacterium tuberculosis; C107475:Esx1 protein, mouse; D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C072681:Mycobacterium tuberculosis antigens