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Increased Regulatory versus Effector T Cell Development Is Associated with Thymus Atrophy in Mouse Models of Multiple Myeloma¹

Ayelet Laronne-Bar-On^*, Dov Zipori^2,* and Nechama Haran-Ghera

^* Department of Molecular Cell Biology and Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs) play a central role in cancer tolerance. However, mechanisms leading to their accumulation in cancer remain unknown. Although the thymus is the main site of Treg development, thymic contribution to Treg expansion in cancer has not been directly examined. Herein, we used two murine models of multiple myeloma (MM), 5T2 MM and 5T33 MM, to examine Treg accumulation in peripheral lymphoid organs, including spleen, lymph nodes, bone marrow, and blood, and to explore thymic Treg development during malignancy. We found that peripheral ratios of suppressive-functional Tregs increased in both models of MM-inflicted mice. We found that thymic ratios of Treg development in MM increased, in strong association with thymus atrophy and altered developmental processes in the thymus. The CD4⁺CD8⁺ double-positive population, normally the largest thymocyte subset, is significantly decreased, whereas the CD4^–CD8^– double-negative population is increased. Administration of thymocytes from MM-inflicted mice compared with control thymocytes resulted in increased progression of the disease, and this effect was shown to be mediated by Tregs in the thymus of MM-inflicted mice. Our data suggest that increased ratios of Treg development in the thymus may contribute to disease progression in MM-inflicted mice.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant (to D.Z.) from the Israel Cancer Research Fund and by a grant from the Wolfson Family Charitable Trust, London, on tumor cell diversity.

² Address correspondence and reprint requests to Dr. Dov Zipori, Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel. E-mail address: dov.zipori{at}weizmann.ac.il

³ Abbreviations used in this paper: BM, bone marrow; DN, double negative; DP, double positive; GITR, glucocorticoid-induced TNF receptor; LN, lymph nodes; MFI, mean fluorescence intensity; MM, multiple myeloma; nTreg, naturally occurring Treg; PB, peripheral blood; SP, single positive; Teff, effector T cell; Treg, regulatory T cell; VEGF, vascular endothelial growth factor.