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Naive Precursors of Human Regulatory T Cells Require FoxP3 for Suppression and Are Susceptible to HIV Infection¹

Amanda K. Antons^*, Rui Wang^2,, Kyra Oswald-Richter^2,*, Michelle Tseng, Christopher W. Arendt, Spyros A. Kalams^*, and Derya Unutmaz^3,

^* Department of Microbiology and Immunology and Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; Department of Microbiology, New York School of Medicine, New York, NY 10016; and Oncology Department, Sanofi-Aventis, Bridgewater, NJ 08807

CD4⁺CD25⁺ human regulatory T cells (T_reg cells), which express the transcription factor FoxP3, suppress T cell activation. In this study, we sought to define cellular and molecular mechanisms of human T_reg cell differentiation. A subset of human naive CD4⁺ T cells that are CD25⁺ express high levels of FoxP3. We show that upon activation through the TCR, these FoxP3-expressing naive T cells (termed T_Nreg cells) greatly expand in vitro. Expanded T_Nreg cells acquire a full T_reg phenotype with potent suppressive activity and display low IL-2 production upon TCR stimulation. T_Nreg cells in which FoxP3 expression was reduced through RNA interference lost their suppressive activity, but retained their low IL-2 secretion in response to TCR stimulation. Furthermore, in support of the notion that T_Nreg cells represent a separate lineage of naive cells, we found that they were more susceptible to HIV infection as compared with naive CD4⁺ T cells. Based on these findings, we propose that T_Nreg cells are precursors for human T_reg cells and that these cells require a high level of FoxP3 expression to maintain their suppressive function. Accordingly, modulation of T_Nreg cell numbers during infections such as HIV may disrupt human T_reg cell development, and contribute to chronic immune activation.

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 support by National Institutes of Health Grant R01 AI065303 (to D.U.).

² R.W. and K.O.-R. contributed equally.

³ Address correspondence and reprint requests to Dr. Derya Unutmaz, Department of Microbiology, New York School of Medicine, Smilow Research Center, 522 First Avenue, Smilow Building 10th Floor, New York, NY 10016. E-mail address: Derya{at}mac.com

⁴ Abbreviations used in this paper: T_reg, regulatory T cell; GITR, glucocorticoid-induced TNFR; T_N, naive CD4⁺ T cell; T_Nreg, FoxP3⁺CD25⁺ naive T cell; T_M, memory CD4⁺ T cell; DC, dendritic cell; SEB, staphylococcal enterotoxin B; shRNA, short hairpin RNA; CBA, cytometric bead array; VSV-G, vesicular stomatitis virus glycoprotein; MOI, multiplicity of infection; RNAi, RNA interference; IFU, infectious unit.

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