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Infection and Immunity, September 2008, p. 4199-4205, Vol. 76, No. 9
0019-9567/08/$08.00+0     doi:10.1128/IAI.00307-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Bacterial Protein Secretion Is Required for Priming of CD8⁺ T Cells Specific for the Mycobacterium tuberculosis Antigen CFP10

Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School,¹ Program in Immunology, Harvard Medical School,² Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115³

Received 7 March 2008/ Returned for modification 25 April 2008/ Accepted 25 June 2008

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.

Published ahead of print on 30 June 2008.

Editor: J. L. Flynn