4.6 Article

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

Journal

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
Volume 52, Issue 6, Pages 3321-3333

Publisher

ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.10-6522

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Funding

  1. Public Health Service [EY014900, EY019896]
  2. Discovery Eye Foundation
  3. Research to Prevent Blindness (RPB)

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PURPOSE. The authors recently reported that Foxp3(+)CD4(+) CD25(+(Bright)) natural regulatory T cells (nT(reg) cells) are abundant in rabbit conjunctiva and suppress herpes simplex virus (HSV)-1-specific CD4(+) and CD8(+) effector T cells (T-eff cells). However, little is known about the overall regulatory mechanisms of these nT(reg) cells. The authors investigate the regulation of conjunctiva-resident nT(reg) cells through Toll-like receptors (TLRs) and their effect on ocular mucosal T-eff cell immunity. METHODS. CD4(+)CD25(+) nT(reg) cells were purified from naive rabbit conjunctivas, and their TLR expression profile was determined. The effects of TLR engagement on nT(reg) cell-mediated suppression of CD4(+) T-eff cells were determined in vitro and in vivo. RESULTS. The authors found that conjunctiva-resident nT(reg) cells express high levels of TLR2 and TLR9; exposure to the TLR2 ligand lipoteichoic acid (LTA) led to the increased activation and proliferation of nT(reg) cells, and the addition of autologous APCs further increased nT(reg) cell expansion; in contrast, the TLR9 ligand CpG(2007) inhibited the proliferation of nT(reg) cells, and the addition of autologous APCs had no effect on such inhibition; nT(reg) cells treated with LTA, but not with CpG(2007), expressed IFN-gamma and IL-10 mRNA, but not TGF-beta; consistent with in vitro data, rabbits immunized by topical ocular drops of HSV-gD peptides + TLR2 ligand (LTA) displayed enhanced CD4(+)CD25(-) T-eff cell immune responses when compared with HSV-gD peptides + TLR9 ligand (CpG(2007)). CONCLUSIONS. Although conjunctiva-resident CD4(+)CD25(+) nT(reg) 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 (CpG(200); P > 0.005). These findings will likely help optimize the topical ocular administration of immunotherapies. (Invest Ophthalmol Vis Sci. 2011;52:3321-3333) DOI:10.1167/iovs.10-6522

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