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CTLA4 Expression Is an Indicator and Regulator of Steady-State CD4⁺FoxP3⁺ T Cell Homeostasis¹

Anita L. Tang^*, John R. Teijaro^*, Modesta N. Njau^*, Smita S. Chandran^*, Agnes Azimzadeh^*, Steven G. Nadler, David M. Rothstein and Donna L. Farber^2,*

^* Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201; Immunology and Inflammation Drug Discovery, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543; and Department of Medicine, Yale University School of Medicine, New Haven, CT 06510

The presence of FoxP3⁺ regulatory T cells (Tregs) is necessary for control of deleterious immune responses in the steady state; however, mechanisms for maintaining the frequency and quality of endogenous Tregs are not well defined. In this study, we used in vivo modulators of the CD28 and CTLA4 pathways administered to intact mice to reveal mechanisms controlling the homeostasis and phenotype of endogenous Tregs. We demonstrate that expression of the negative costimulatory regulator CTLA4 on FoxP3⁺ Tregs in vivo is a direct consequence of their rapid, perpetual homeostasis. Up-regulation of CTLA4 expression occurs only on FoxP3⁺ Tregs undergoing extensive proliferation and can be abrogated by inhibiting the CD28 pathway, coinciding with a reduction in FoxP3⁺ Treg proliferation and frequency. We further demonstrate that CTLA4 negatively regulates steady-state Treg homeostasis, given that inhibiting CTLA4 signaling with an anti-CTLA4 blocking Ab greatly enhances Treg proliferation and overall Treg frequency. Our findings provide new insight into the origin and role of CTLA4 expression on natural FoxP3⁺ Tregs and reveal opposing effects of costimulation modulators on the steady-state level and quality of Tregs, with implications regarding their effects on endogenous Tregs in patients receiving immunotherapy.

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 from Bristol-Myers Squibb and by National Institutes of Health Grant AI050632 (to D.L.F.).

² Address correspondence and reprint requests to Dr. Donna L. Farber, Department of Surgery, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201. E-mail address: dfarber{at}smail.umaryland.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; GITR, glucocorticoid-induced tumor necrosis factor receptor; MFI, mean fluorescence intensity.