Perforin-Mediated Cytotoxicity Is Critical for Surveillance of Spontaneous Lymphoma

doi:10.1084/jem.192.5.755

Published online 5 September 2000.

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© The Rockefeller University Press, 0022-1007/2000/9/755/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 5, September 5, 2000 755-760

Brief Definitive Report

Perforin-Mediated Cytotoxicity Is Critical for Surveillance of Spontaneous Lymphoma

Mark J. Smyth^a, Kevin Y.T. Thia^a, Shayna E.A. Street^a, Duncan MacGregor^b, Dale I. Godfrey^c, and Joseph A. Trapani^a

^a Austin Research Institute, Heidelberg, 3084, Victoria, Australia
^b Department of Anatomical Pathology, Austin and Repatriation Medical Centre, Heidelberg, 3084, Victoria, Australia
^c Department of Immunology and Pathology, Monash University Medical School, Prahran, 3181 Victoria, Australia
Cancer Immunology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett Street, Victoria, Australia, 8006.61-3-9656-141161-3-9656-1111

m.smyth{at}pmci.unimelb.edu.au

Immune surveillance by cytotoxic lymphocytes against cancerhas been postulated for decades, but direct evidence for therole of cytotoxic lymphocytes in protecting against spontaneousmalignancy has been lacking. As the rejection of many experimentalcancers by cytotoxic T lymphocytes and natural killer cellsis dependent on the pore-forming protein perforin (pfp), weexamined pfp-deficient mice for increased cancer susceptibility.Here we show that pfp-deficient mice have a high incidence ofmalignancy in distinct lymphoid cell lineages (T, B, NKT), indicatinga specific requirement for pfp in protection against lymphomagenesis.The susceptibility to lymphoma was accentuated by simultaneouslack of expression of the p53 gene, mutations in which alsocommonly predispose to human malignancies, including lymphoma.In contrast, the incidence and age of onset of sarcoma was unaffectedin p53-deficient mice. Pfp-deficient mice were at least 1,000-foldmore susceptible to these lymphomas when transplanted, comparedwith immunocompetent mice in which tumor rejection was controlledby CD8⁺ T lymphocytes. This study is the first that implicatesdirect cytotoxicity by lymphocytes in regulating lymphomagenesis.

Key Words: tumor immunity • perforin • lymphoma • cytotoxic T lymphocyte • surveillance

M.J. Smyth and K.Y.T. Thia contributed equally to this work.

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