Mycobacterium tuberculosis-specific CD8+ T cells require perforin to kill target cells and provide protection in vivo

JS Woodworth, Y Wu, SM Behar - The Journal of Immunology, 2008 - journals.aai.org
JS Woodworth, Y Wu, SM Behar
The Journal of Immunology, 2008journals.aai.org
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 …
Abstract
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-γ and specifically defines the CD8+ cytolytic mechanisms utilized and required in vivo.
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