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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2142-2151. Prepublished online as a Blood First Edition Paper on December 20, 2007; DOI 10.1182/blood-2007-08-105221. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-08-105221v1 111/4/2142    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Goping, I. S. Articles by Bleackley, R. C. PubMed PubMed Citation Articles by Goping, I. S. Articles by Bleackley, R. C. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Cytotoxic T lymphocytes overcome Bcl-2 inhibition: target cells contribute to their own demise Ing Swie Goping1, Tracy Sawchuk1, Aja Rieger1, Irene Shostak1, and R. Chris Bleackley1 1 Department of Biochemistry, University of Alberta, Edmonton, AB, Canada Cytotoxic T lymphocytes (CTLs) eliminate pathogenic cells in large part through the activity of the serine protease granzyme B (grB). However, while the apoptotic activity of grB is blocked by over-expression of Bcl-2, CTLs can still kill target cells through an ill-defined Bcl-2–independent pathway. In this report, we have identified key modulators of this Bcl-2–independent cell-death pathway, which is induced by CTLs and not purified components. Surprisingly, activation of this pathway is reliant on grB. Furthermore, this novel pathway requires mitochondrial contribution through triggering of permeability transition and generation of reactive oxygen species, yet is functional in the absence of Bax/Bak. This pathway stimulates movement of target cell mitochondria toward the point of contact with the CTLs and importantly, inhibition of this directed movement attenuates killing. Therefore, we propose that CTLs initiate a target cell response that activates multiple mitochondrial pathways. This ensures that CTLs can eliminate those target cells that have compromised apoptotic potential due to overexpression of Bcl-2. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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