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Regulatory T Cells Prevent CD8 T Cell Maturation by Inhibiting CD4 Th Cells at Tumor Sites¹

Nathalie Chaput^2,*, Guillaume Darrasse-Jèze^2,*, Anne-Sophie Bergot^*, Corinne Cordier, Stacie Ngo-Abdalla^*, David Klatzmann^* and Orly Azogui^3,*

^* Laboratoire de Biologie et Thérapeutique des Pathologies Immunitaires, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 7087, Université Pierre et Marie Curie-Paris 6, Hôpital Pitié-Salpêtrière, Paris, France; and Institut National de la Santé et de la Recherche Médicale, Institut Fédératif de Recherche 94, Hopital Necker Enfants Malades, Paris, France

Natural regulatory T cells (Tregs) are present in high frequencies among tumor-infiltrating lymphocytes and in draining lymph nodes, supposedly facilitating tumor development. To investigate their role in controlling local immune responses, we analyzed intratumoral T cell accumulation and function in the presence or absence of Tregs. Tumors that grew in normal BALB/c mice injected with the 4T1 tumor cell line were highly infiltrated by Tregs, CD4 and CD8 cells, all having unique characteristics. Most infiltrating Tregs expressed low levels of CD25Rs and Foxp3. They did not proliferate even in the presence of IL-2 but maintained a strong suppressor activity. CD4 T cells were profoundly anergic and CD8 T cell proliferation and cytotoxicity were severely impaired. Depletion of Tregs modified the characteristics of tumor infiltrates. Tumors were initially invaded by activated CD4⁺CD25^– T cells, which produced IL-2 and IFN-. This was followed by the recruitment of highly cytotoxic CD8⁺ T cells at tumor sites leading to tumor rejection. The beneficial effect of Treg depletion in tumor regression was abrogated when CD4 helper cells were also depleted. These findings indicate that the massive infiltration of tumors by Tregs prevents the development of a successful helper response. The Tregs in our model prevent Th cell activation and subsequent development of efficient CD8 T cell activity required for the control of tumor growth.

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 in part by University Pierre and Marie Curie (Paris VI) and the Centre National de la Recherche Scientifique.

² N.C. and G.D.-J. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Orly Azogui, Laboratoire de Biologie et Thérapeutique des Pathologies Immunitaires, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 7087, Université Pierre et Marie Curie-Paris 6, Hôpital Pitié-Salpêtrière, 75013 Paris, France. E-mail address: oazogui{at}chups.jussieu.fr

⁴ Abbreviations used in this paper: DLN, draining lymph node; Treg, regulatory T cell; GITR, glucocorticoid-induced TNFR; TIL, tumor-infiltrating lymphocyte; NLN, normal lymph node; Tr1, T regulatory 1.

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