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Blood, 15 August 2007, Vol. 110, No. 4, pp. 1184-1190. Prepublished online as a Blood First Edition Paper on May 2, 2007; DOI 10.1182/blood-2007-02-072850. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-02-072850v1 110/4/1184    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Voskoboinik, I. Articles by Trapani, J. A. Search for Related Content PubMed PubMed Citation Articles by Voskoboinik, I. Articles by Trapani, J. A. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function Ilia Voskoboinik1,2, Vivien R. Sutton1, Annette Ciccone1, Colin M. House3, Jenny Chia1, Phillip K. Darcy1, Hideo Yagita4, and Joseph A. Trapani1,5 1 Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Australia; 2 Department of Genetics, The University of Melbourne, Parkville, Australia; 3 Cancer Genomics Program, Peter MacCallum Cancer Centre, East Melbourne, Australia; 4 Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; and 5 Department of Pathology, The University of Melbourne, Parkville, Australia Perforin (PRF), a pore-forming protein expressed in cytotoxic lymphocytes, plays a key role in immune surveillance and immune homeostasis. The A91V substitution has a prevalence of 8% to 9% in population studies. While this variant has been suspected of predisposing to various disorders of immune homeostasis, its effect on perforin's function has not been elucidated. Here we complemented, for the first time, the cytotoxic function of perforin-deficient primary cytotoxic T lymphocytes (CTLs) with wild-type (hPRF-WT) and A91V mutant (hPRF-A91V) perforin. The cytotoxicity of hPRF-A91V–expressing cells was about half that of hPRF-WT–expressing counterparts and coincided with a moderate reduction in hPRF-A91V expression. By contrast, the reduction in cytotoxic function was far more pronounced (more than 10-fold) when purified proteins were tested directly on target cells. The A91V substitution can therefore be manifested by abnormalities at both the lymphocyte (presynaptic) and target cell (postsynaptic) levels. However, the severe intrinsic defect in activity can be partly rescued by expression in the physiological setting of an intact CTL. These findings provide the first direct evidence that hPRF-A91V is functionally abnormal and provides a rationale for why it may be responsible for disordered immune homeostasis if inherited with another dysfunctional perforin allele. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Chia, K. P. Yeo, J. C. Whisstock, M. A. Dunstone, J. A. Trapani, and I. Voskoboinik Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer PNAS, June 16, 2009; 106(24): 9809 - 9814. [Abstract] [Full Text] [PDF] R. Urrea Moreno, J. Gil, C. Rodriguez-Sainz, E. Cela, V. LaFay, B. Oloizia, A. B. Herr, J. Sumegi, M. B. Jordan, and K. A. Risma Functional assessment of perforin C2 domain mutations illustrates the critical role for calcium-dependent lipid binding in perforin cytotoxic function Blood, January 8, 2009; 113(2): 338 - 346. [Abstract] [Full Text] [PDF] A Trizzino, U z. Stadt, I Ueda, K Risma, G Janka, E Ishii, K Beutel, J Sumegi, S Cannella, D Pende, et al. Genotype phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations J. Med. Genet., January 1, 2008; 45(1): 15 - 21. [Abstract] [Full Text] [PDF] C. J. Rosado, A. M. Buckle, R. H. P. Law, R. E. Butcher, W.-T. Kan, C. H. Bird, K. Ung, K. A. Browne, K. Baran, T. A. Bashtannyk-Puhalovich, et al. A Common Fold Mediates Vertebrate Defense and Bacterial Attack Science, September 14, 2007; 317(5844): 1548 - 1551. [Abstract] [Full Text] [PDF]

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