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Blood, 1 May 2006, Vol. 107, No. 9, pp. 3665-3668.
Prepublished online as a Blood First Edition Paper on January 12, 2006; DOI 10.1182/blood-2005-03-1140.
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Submitted March 21, 2005
Accepted November 24, 2005
A family with Papillon-Lefevre Syndrome reveals a requirement for Cathepsin C in Granzyme B activation and NK cell cytolytic activity
Josephine L Meade, Erika A de Wynter, Peter Brett, Saghira Malik Sharif, C. Geoffrey Woods, Alexander F Markham, and Graham P Cook*
Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom
Eastman Dental Institute, University College, London, United Kingdom
Department of Clinical Genetics, St. James's University Hospital, Leeds, United Kingdom
Cancer Research UK, London, United Kingdom
* Corresponding author; email: g.p.cook{at}leeds.ac.uk.
Activation of granzyme B, a key cytolytic effector molecule of NK cells, requires removal of an N-terminal pro-domain. In mice, cathepsin C is required for granzyme processing and normal NK cell cytolytic function, whereas in patients with Papillon-Lefevre syndrome (PLS), loss-of-function mutations in cathepsin C do not affect lymphokine activated killer (LAK) cell function. Here we demonstrate that resting PLS NK cells do have a cytolytic defect and fail to induce the caspase cascade in target cells. NK cells from these patients contain inactive granzyme B, indicating that cathepsin C is required for granzyme B activation in unstimulated human NK cells. However, in vitro activation of PLS NK cells with IL-2 restores cytolytic function and granzyme B activity by a cathepsin C-independent mechanism. This is the first documented example of a human mutation affecting granzyme B activity and highlights the importance of cathepsin C in human NK cell function.
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