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Gargi Dasgupta, Aziz Alami Chentoufi, Sylvaine You, Payam Falatoonzadeh, Lourie Ann A. Urbano, Ayesha Akhtarmalik, Kimberly Nguyen, Lilit Ablabutyan, Anthony B. Nesburn, 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(6):3321-3333. doi: 10.1167/iovs.10-6522.
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The authors recently reported that Foxp3+CD4+ CD25+(Bright) “natural” regulatory T cells (nTreg cells) are abundant in rabbit conjunctiva and suppress herpes simplex virus (HSV)-1–specific CD4+ and CD8+ effector T cells (Teff cells). However, little is known about the overall regulatory mechanisms of these nTreg cells. The authors investigate 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 naive rabbit conjunctivas, and their TLR expression profile was determined. The effects of TLR engagement on nTreg cell-mediated suppression of CD4+ Teff cells were determined in vitro and in vivo.
The authors found that conjunctiva-resident nTreg cells express high levels of TLR2 and TLR9; exposure to the TLR2 ligand lipoteichoic acid (LTA) led to the increased activation and proliferation of nTreg cells, and the addition of autologous APCs further increased nTreg cell expansion; in contrast, the TLR9 ligand CpG2007 inhibited the proliferation of nTreg cells, and the addition of autologous APCs had no effect on such inhibition; nTreg cells treated with LTA, but not with CpG2007, expressed IFN-γ and IL-10 mRNA, but not TGF-β; 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 with 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 after the administration of TLR2 ligand (LTA; P < 0.005) than of TLR9 ligand (CpG200; P > 0.005). These findings will likely help optimize the topical ocular administration of immunotherapies.
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