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A. B. Nesburn, G. Dasgupta, A. Chentoufi, I. Bettahi, S. L. Wechsler, L. BenMohamed; Conjunctiva Resident CD4+CD25+ Regulatory T cells Express Toll Like Receptor (TLR)2 and TLR9 and Their Respective Ligands Lipoteichoic Acid and Cytosine-Phosphate-Guanine, Enhance Their Suppressive Capacity. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2521. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
We recently reported that functional Foxp3+CD4+CD25+(Bright) "natural" regulatory T cells (Treg cells) are abundant in naïve rabbit conjunctiva, and suppress virus-specific CD4+ and CD8+ effector T cells during ocular HSV1 infection. Although TLRs can modulate Treg function, their role in conjunctiva Treg function remains to be elucidated.
60 conjunctivas were harvested from naive rabbits. Treg cells were purified from conjunctivas by immuno-magnetic sorting and TLR profiles examined by FACS. Purified Treg cells were exposed in vitro to TLR ligands, LTA (TLR2), LPS (TLR4) and CpG (TLR9) and their stimulation was assessed by CFSE. The effect of adding antigen presenting cells (APCs) to TLR-ligand treated Treg cells was determined. To evaluate the role of Tregs on ocular surface immune responses in vivo, naïve rabbits were depleted of Tregs by sc injections of cyclophosphamide (50 µg; x6) and then immunized by topical ocular applications of 100 ug HSV-gD peptides + 25 ug TLR9 ligand (CpG) every 10 days (x3). Non-depleted, immunized rabbits were used as controls. Ten days later, immune T effector cells (Teff cells) were harvested and stimulated in vitro with the same HSV-gD peptides and Teff cell responses measured.
Conjunctival Treg cells expressed high levels of TLRs 2 and 9, but not TLRs 3, 4 or 8. Treg cell proliferation was induced by TLR ligands LTA (TLR2) and CpG (TLR9), but not by LPS (TLR4). Addition of autologous APCs improved TLR-mediated proliferative responses. Cyclophosphamide significantly depleted local (conjunctiva) and systemic (PBMC) Treg cells, while CD8+ T cell counts were unaffected. Depletion of Treg cells enhanc
This is the first report showing that TLRs 2 and 9 are highly expressed on conjunctiva Treg cells. They were functionally active and acted with APCs to fine tune HSV-specific ocular mucosal Teff cell responses. Thus, depletion of conjunctival Treg cells or interference with TLR2 and TLR9 function may be useful to enhance the efficacy of topical ocular immunization.
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