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Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115
Optimal immunity to Mycobacterium tuberculosis (Mtb) infection requires CD8+ T cells, and several current Mtb vaccine candidates are being engineered to elicit enhanced CD8+ T cell responses. However, the function of these T cells and the mechanism by which they provide protection is still unknown. We have previously shown that CD8+ T cells specific for the mycobacterial Ags CFP10 and TB10.4 accumulate in the lungs of mice following Mtb infection and have cytolytic activity in vivo. In this study, we determine which cytolytic pathways are used by these CD8+ T cells during Mtb infection. We find that Mtb-specific CD8+ T cells lacking perforin have reduced cytolytic capacity in vivo. In the absence of perforin, the residual cytolytic activity is CD95 and TNFR dependent. This is particularly true in Mtb-infected lung tissue where disruption of both perforin and CD95 eliminates target cell lysis. Moreover, adoptive transfer of immune CD8+ T cells isolated from wild-type, but not perforin-deficient mice, protect recipient mice from Mtb infection. We conclude that CD8+ T cells elicited following Mtb infection use several cytolytic pathways in a hierarchical and compensatory manner dominated by perforin-mediated cytolysis. Finally, although several cytolytic pathways are available, adoptively transferred Mtb-specific CD8+ T cells require perforin-mediated cytolysis to protect animals from infection. These data show that CD8+ T cell-mediated protection during Mtb infection requires more than the secretion of IFN-
and specifically defines the CD8+ cytolytic mechanisms utilized and required in vivo.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant R01 AI067731 (to S.M.B.).
2 Address correspondence and reprint requests to Dr. Samuel M. Behar, Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Smith Building, Room 516C, One Jimmy Fund Way, Boston, MA 02115. E-mail address: sbehar{at}rics.bwh.harvard.edu
3 Abbreviations used in this paper: Mtb, Mycobacterium tuberculosis; CMTMR, chloromethyl-benzoyl-amino-tetramethylrhodamine; Pfn, perforin; WT, wild type; SA, streptavidin.
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  T. Einarsdottir, E. Lockhart, and J. L. Flynn Cytotoxicity and Secretion of Gamma Interferon Are Carried Out by Distinct CD8 T Cells during Mycobacterium tuberculosis Infection Infect. Immun., October 1, 2009; 77(10): 4621 - 4630. [Abstract] [Full Text] [PDF]
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