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Blood, 1 December 2007, Vol. 110, No. 12, pp. 3968-3977. Prepublished online as a Blood First Edition Paper on August 21, 2007; DOI 10.1182/blood-2007-01-071167. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-01-071167v1 110/12/3968    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 Citing Articles via Google Scholar Google Scholar Articles by Brenner, D. Articles by Arnold, R. Search for Related Content PubMed PubMed Citation Articles by Brenner, D. Articles by Arnold, R. Related Collections Apoptosis Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Caspase-cleaved HPK1 induces CD95L-independent activation-induced cell death in T and B lymphocytes Dirk Brenner1, Alexander Golks1, Mareike Becker1, Wolfgang Müller1, Christian R. Frey1, Rostislav Novak2, Doron Melamed2, Friedemann Kiefer3, Peter H. Krammer1, and Rüdiger Arnold1 1 Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany; 2 Department of Immunology, Faculty of Medicine, Technion, Haifa, Israel; 3 Max-Planck-Institute for Molecular Biomedicine, Münster, Germany Life and death of peripheral lymphocytes is strictly controlled to maintain physiologic levels of T and B cells. Activation-induced cell death (AICD) is one mechanism to delete superfluous lymphocytes by restimulation of their immunoreceptors and it depends partially on the CD95/CD95L system. Recently, we have shown that hematopoietic progenitor kinase 1 (HPK1) determines T-cell fate. While full-length HPK1 is essential for NF-B activation in T cells, the C-terminal fragment of HPK1, HPK1-C, suppresses NF-B and sensitizes toward AICD by a yet undefined cell death pathway. Here we show that upon IL-2–driven expansion of primary T cells, HPK1 is converted to HPK1-C by a caspase-3 activity below the threshold of apoptosis induction. HPK1-C se-lectively blocks induction of NF-B–dependent antiapoptotic Bcl-2 family members but not of the proapoptotic Bcl-2 family member Bim. Interestingly, T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of the CD95/CD95L system but involving caspase-9. Knock down of HPK1/HPK1-C or Bim by small interfering RNA shows that CD95L-dependent and HPK1/HPK1-C–dependent cell death pathways complement each other in AICD of primary T cells. Our results define HPK1-C as a suppressor of antiapoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent AICD of lymphocytes. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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