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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.
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Submitted February 6, 2007
Accepted April 25, 2007
Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both pre- and post-synaptic defects in function
Ilia Voskoboinik*, Vivien R Sutton, Annette Ciccone, Colin House, Jenny Chia, Phillip K Darcy, Hideo Yagita, and Joseph A Trapani
Department of Genetics, The University of Melbourne, Parkville, Australia
Cancer Immunology Research Program, Peter MacCallum Cancer Centre, Melbourne, Australia
Cancer Genomics Program, Peter MacCallum Cancer Centre, Melbourne, Australia
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
Department of Pathology, The University of Melbourne, Melbourne, Australia
* Corresponding author; email: ilia.voskoboinik{at}petermac.org.
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 8-9% 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 (CTL) 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 (pre-synaptic) and target cell (post-synaptic) 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.
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