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Fas ligand–mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas

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Abstract

Loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1) or deregulated expression of the oncogene BCL6 occurs in a large proportion of diffuse large B cell lymphoma (DLBCL) cases. However, targeted mutation of either gene in mice leads to only slow and infrequent development of malignant lymphoma, and despite frequent mutation of BCL6 in activated B cells of healthy individuals, lymphoma development is rare. Here we show that T cells prevent the development of overt lymphoma in mice caused by Blimp1 deficiency or overexpression of Bcl6 in the B cell lineage. Impairment of T cell control results in rapid development of DLBCL-like disease, which can be eradicated by polyclonal CD8+ T cells in a T cell receptor–, CD28- and Fas ligand–dependent manner. Thus, malignant transformation of mature B cells requires mutations that impair intrinsic differentiation processes and permit escape from T cell–mediated tumor surveillance.

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Figure 1: Expansion of a pre-plasmablast population in the absence of Blimp1.
Figure 2: Accelerated lymphoma development in Blimp1-mutant T cell–deficient mice.
Figure 3: Molecular profiles of B cell lymphomas.
Figure 4: Bcl6 overexpression in the absence of T cells drives rapid B cell lymphoma development.
Figure 5: Polyclonal CD8+ T cells can eradicate B lymphoma cells in a TCR- and CD28-dependent manner.
Figure 6: CD8+ T cells eradicate B lymphoma cells by activating the FasL-Fas apoptotic pathway.

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  • 30 May 2014

    In the version of this article initially published, the percentages in the top row of Figure 1c were incorrect. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank L. Pasqualucci (Columbia University) for Bcl6-transgenic mice, D. Yu (Monash University) for Cd28−/− mice, M. Reth (Albert-Ludwigs-Universität) for Cd79a-Cre mice, L. Wu (Walter and Eliza Hall Institute of Medical Research (WEHI)) for MHC-I antibodies and A. Brooks (University of Melbourne) for antibodies, D. Gray (WEHI) for TCR antibodies, J. Markham for help with the statistical analysis, and P. Schneider (University of Lausanne) for the Fc-FasL. This work was supported by grants and fellowships from the National Health and Medical Research Council of Australia (G.T.B., L.M.C., S.L.N., D.M.T., A.K., A.S., M.J.S. and L.A.O.), the Australia Research Council (A.K., S.L.N.), the Sylvia and Charles Viertel Foundation and the Howard Hughes Medical Institute (A.K., G.T.B.), the Cancer Council Victoria (D.Z.), Cancer Australia and the Cancer Council New South Wales (L.A.O.), and the Leukemia & Lymphoma Society (A.K., L.A.O. and A.S.). This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government National Health and Medical Research Council Independent Research Institute Infrastructure Support scheme.

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S.A.-S., D.Z. and N.J.B. performed and analyzed the majority of the experiments; A.K.S., L.R., A.E.A. and J.W. conducted and analyzed experiments; F.M. and G.T.B. did infection experiments; L.M.C., L.A.O., A.S., M.J.S., R.J. contributed to the design of experiments; D.M.T. and S.L.N. contributed to the design of the study and the writing of the manuscript; A.K. designed the study, analyzed data and wrote the manuscript.

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Correspondence to Axel Kallies.

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Afshar-Sterle, S., Zotos, D., Bernard, N. et al. Fas ligand–mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas. Nat Med 20, 283–290 (2014). https://doi.org/10.1038/nm.3442

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