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Anthony B. Nesburn, Gargi Dasgupta, Aziz A. Chentoufi, Payam Falatoonzadeh, Lourie A. Urbano, Ayesha Akhtarmalik, Kimberly Nguyen, Lilit Ablabutyan, Lbachir BenMohamed; Engagement of TLR2 Reverses the Suppressor Function of Conjunctiva CD4+CD25+ Regulatory T Cells, and Promotes Herpes Simplex Virus Epitope-Specific CD4+CD25- Effector T Cell Responses. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1930.
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We recently reported that Foxp3+CD4+CD25+(Bright) "natural" regulatory T cells (nTreg cells) are abundant in rabbit conjunctiva and suppress HSV-1-specific CD4+ and CD8+ effector T cells (Teff cells). However, little is known about these nTreg cells and their regulatory mechanisms. This study investigates the regulation of conjunctiva resident nTreg cells through Toll-like receptors (TLRs) and their effect on ocular mucosal Teff cell immunity.
CD4+CD25+ nTreg cells were purified from naïve rabbit conjunctivas and their TLR expression profile was determined. The effects of TLRs engagement on nTreg cell-mediated suppression of CD4+ Teff cells were determined in vitro and in vivo.
We found that: (i) Conjunctiva resident nTreg cells express high levels of TLR2 and TLR9; (ii) Exposure to TLR2 ligand, lipoteichoic acid (LTA), led to increased activation and proliferation of nTreg cells and the addition of autologous APCs further increased nTreg cell expansion; (iii) In contrast, the TLR9 ligand, CpG2007, inhibited the proliferation of nTreg cells, and the addition of autologous APCs had no effect on such inhibition; (iv) nTreg cells treated with LTA, but not with CpG2007, expressed IFN-γ and IL-10 mRNA, but not TGF-β; (v) Consistent with in vitro data, rabbits immunized by topical ocular drops of HSV-gD peptides + TLR2 ligand (LTA), displayed enhanced CD4+CD25- Teff cell immune responses, when compared to HSV-gD peptides + TLR9 ligand (CpG2007).
Although conjunctiva resident CD4+CD25+ nTreg cells express high level of TLR2 and TLR9, their suppressive function is more significantly reversed following administration of TLR2 ligand (LTA, p <0.005) than TLR9 ligand (CpG200, p >0.005). The findings will likely help optimize the topical ocular administration of immuno-therapies.
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