The Journal of Experimental Medicine
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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. Smytha, Kevin Y.T. Thiaa, Shayna E.A. Streeta, Duncan MacGregorb, Dale I. Godfreyc, and Joseph A. Trapania

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 cancer has been postulated for decades, but direct evidence for the role of cytotoxic lymphocytes in protecting against spontaneous malignancy has been lacking. As the rejection of many experimental cancers by cytotoxic T lymphocytes and natural killer cells is dependent on the pore-forming protein perforin (pfp), we examined pfp-deficient mice for increased cancer susceptibility. Here we show that pfp-deficient mice have a high incidence of malignancy in distinct lymphoid cell lineages (T, B, NKT), indicating a specific requirement for pfp in protection against lymphomagenesis. The susceptibility to lymphoma was accentuated by simultaneous lack of expression of the p53 gene, mutations in which also commonly predispose to human malignancies, including lymphoma. In contrast, the incidence and age of onset of sarcoma was unaffected in p53-deficient mice. Pfp-deficient mice were at least 1,000-fold more susceptible to these lymphomas when transplanted, compared with immunocompetent mice in which tumor rejection was controlled by CD8+ T lymphocytes. This study is the first that implicates direct 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.

© 2000 The Rockefeller University Press


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