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Journal of Virology, July 2007, p. 7647-7661, Vol. 81, No. 14
0022-538X/07/$08.00+0     doi:10.1128/JVI.00294-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Functional Foxp3⁺ CD4⁺ CD25^(Bright+) "Natural" Regulatory T Cells Are Abundant in Rabbit Conjunctiva and Suppress Virus-Specific CD4⁺ and CD8⁺ Effector T Cells during Ocular Herpes Infection

Anthony B. Nesburn,¹ Ilham Bettahi,¹ Gargi Dasgupta,¹ Alami Aziz Chentoufi,¹ Xiuli Zhang,¹ Sylvaine You,² Naoyuki Morishige,¹ Andrew J. Wahlert,¹ Donald J. Brown,¹ James V. Jester,¹ Steven L. Wechsler,¹ and Lbachir BenMohamed^1,3*

Cellular and Molecular Immunology Laboratory, The Eye Institute, University of California, Irvine, Irvine, California 92697-4375,¹ INSERM U580, Hôpital Necker-Enfants Malades, 161 Rue de Sèvres, 75015 Paris, France,² Center for Immunology, University of California, Irvine, Irvine, California 92697-1450³

Received 11 February 2007/ Accepted 25 April 2007

We studied the phenotype and distribution of "naturally" occurring CD4⁺ CD25⁺ T regulatory cells (CD4⁺ CD25⁺ nT_reg cells) resident in rabbit conjunctiva, the main T-cell inductive site of the ocular mucosal immune system, and we investigated their suppressive capacities using herpes simplex virus type 1 (HSV-1)-specific effector T (T_eff) cells induced during ocular infection. The expression of CD4, CD25, CTLA4, GITR, and Foxp3 was examined by reverse transcription-PCR, Western blotting, and fluorescence-activated cell sorter analysis in CD45⁺ pan-leukocytes isolated from conjunctiva, spleen, and peripheral blood monocyte cells (PBMC) of HSV-1-infected and uninfected rabbits. Normal conjunctiva showed a higher frequency of CD4⁺ CD25^(Bright+) T cells than did spleen and PBMC. These cells expressed high levels of Foxp3, GITR, and CTLA4 molecules. CD4⁺ CD25^(Bright+) T cells were localized continuously along the upper and lower palpebral and bulbar conjunctiva, throughout the epithelium and substantia propria. Conjunctiva-derived CD4⁺ CD25^(Bright+) T cells, but not CD4⁺ CD25^(low) T cells, efficiently suppressed HSV-specific CD4⁺ and CD8⁺ T_eff cells. The CD4⁺ CD25^(Bright+) T-cell-mediated suppression was effective on both peripheral blood and conjunctiva infiltrating T_eff cells and was cell-cell contact dependent but independent of interleukin-10 and transforming growth factor ß. Interestingly, during an ocular herpes infection, there was a selective increase in the frequency and suppressive capacity of Foxp3⁺ CD4⁺ CD25^(Bright+) T cells in conjunctiva but not in the spleen or in peripheral blood. Altogether, these results provide the first evidence that functional Foxp3⁺ CD4⁺ CD25^(Bright+) T_reg cells accumulate in the conjunctiva. It remains to be determined whether conjunctiva CD4⁺ CD25⁺ nT_reg cells affect the topical/mucosal delivery of subunit vaccines that stimulate the ocular mucosal immune system.

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* Corresponding author. Mailing address: Cellular and Molecular Immunology Laboratory, University of California Irvine College of Medicine, Bldg. 55, Room 202, Orange, CA 92868. Phone: (714) 456-7371. Fax: (714) 456-5073. E-mail: Lbenmoha{at}uci.edu

Published ahead of print on 2 May 2007.

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Journal of Virology, July 2007, p. 7647-7661, Vol. 81, No. 14
0022-538X/07/$08.00+0     doi:10.1128/JVI.00294-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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