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Journal of Virology, July 2008, p. 6838-6851, Vol. 82, No. 14
0022-538X/08/$08.00+0     doi:10.1128/JVI.00697-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

In Vitro-Generated Antigen-Specific CD4⁺ CD25⁺ Foxp3⁺ Regulatory T Cells Control the Severity of Herpes Simplex Virus-Induced Ocular Immunoinflammatory Lesions

Sharvan Sehrawat,¹ Susmit Suvas,² Pranita P. Sarangi,¹ Amol Suryawanshi,¹ and Barry T. Rouse^1*

Comparative and Experimental Medicine, College of Veterinary Medicine, The University of Tennessee, Knoxville, Tennessee 37996-0845,¹ 305, SEB Department of Biological Science, Oakland University, Rochester, Michigan 48309²

Received 28 March 2008/ Accepted 6 May 2008

Generating and using regulatory T cells (Tregs) to modulate inflammatory disease represents a valuable approach to therapy but has not yet been applied as a means to control virus-induced immunopathological reactions. In this report, we developed a simplified technique that used unfractionated splenocytes as a precursor population and showed that stimulation under optimized conditions for 5 days with solid-phase anti-CD3 monoclonal antibody in the presence of transforming growth factor β (TGF-β) and interleukin-2 could induce up to 90% of CD4⁺ T cells to become Foxp3⁺ and able to mediate suppression in vitro. CD11c⁺ dendritic cells were intricately involved in the conversion process and, once modified in the presence of TGF-β, could convert Foxp3^– CD4⁺ cells into Foxp3⁺ CD4⁺cells by producing TGF-β. The converted cells had undergone cell division, and the majority of them expressed activation markers along with surface molecules that would facilitate their migration into tissue sites. The primary reason for our study was to determine if such in vitro-converted Tregs could be used in vivo to influence the outcome of a virus-induced immunoinflammatory lesion in the eye caused by herpes simplex virus infection. We could show in three separate models of herpetic stromal keratitis that adoptive transfers of in vitro-converted Tregs effectively diminished lesion severity, especially when given in the initial phases of infection. The suppression effect in vivo appeared to be polyspecific. The protocol we have developed could provide a useful additional approach to control virus-induced inflammatory disease.

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* Corresponding author. Mailing address: M409, Walters Life Sciences Bldg., Department of Pathobiology, The University of Tennessee, 1414 Cumberland Ave., Knoxville, TN 37996-0845. Phone: (865) 974-4026. Fax: (865) 974-7817. E-mail: btr{at}utk.edu

Published ahead of print on 14 May 2008.

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Journal of Virology, July 2008, p. 6838-6851, Vol. 82, No. 14
0022-538X/08/$08.00+0     doi:10.1128/JVI.00697-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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