Toll-like receptor 2 controls expansion and function of regulatory T cells
Roger P.M. Sutmuller, … , Mihai G. Netea, Gosse J. Adema
Roger P.M. Sutmuller, … , Mihai G. Netea, Gosse J. Adema
Published February 1, 2006
Citation Information: J Clin Invest. 2006;116(2):485-494. https://doi.org/10.1172/JCI25439.
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Research Article Immunology

Toll-like receptor 2 controls expansion and function of regulatory T cells

Abstract

Tregs play a central role in the suppression of immune reactions and prevention of autoimmune responses harmful to the host. During acute infection, however, Tregs might hinder effector T cell activity directed toward the elimination of the pathogenic challenge. Pathogen recognition receptors from the TLR family expressed by innate immune cells are crucial for the generation of effective immunity. We have recently shown the CD4+CD25+ Treg subset in TLR2–/– mice to be significantly reduced in number compared with WT littermate control mice, indicating a link between Tregs and TLR2. Here, we report that the TLR2 ligand Pam3Cys, but not LPS (TLR4) or CpG (TLR9), directly acts on purified Tregs in a MyD88-dependent fashion. Moreover, when combined with TCR stimulation, TLR2 triggering augmented Treg proliferation in vitro and in vivo and resulted in a temporal loss of the suppressive Treg phenotype in vitro by directly affecting Tregs. Importantly, WT Tregs adoptively transferred into TLR2–/– mice were neutralized by systemic administration of TLR2 ligand during the acute phase of a Candida albicans infection, resulting in a 100-fold reduced C. albicans outgrowth. This demonstrates that in vivo TLR2 also controls the function of Tregs and establishes a direct link between TLRs and the control of immune responses through Tregs.

Authors

Roger P.M. Sutmuller, Martijn H.M.G.M. den Brok, Matthijs Kramer, Erik J. Bennink, Liza W.J. Toonen, Bart-Jan Kullberg, Leo A. Joosten, Shizuo Akira, Mihai G. Netea, Gosse J. Adema

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Figure 8

TLR2 controls Treg suppressor function in vivo.

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TLR2 controls Treg suppressor function in vivo. (A) TLR2 and TCR trigger...
(A) TLR2 and TCR triggering cooperate to induce Treg expansion in vivo. TLR2–/– mice were reconstituted with 2 × 106 freshly isolated and CFSE-labeled OT-II–transgenic Tregs (TCR of OT-II transgenic T cells is Vα2 and specific for the OVA-peptide presented in I-Ab). The reconstituted mice were subsequently challenged i.p. with either PAM (20 μg/mouse) or OVA-peptide [OVA-pep] (10 μg/mouse) alone or with the combination of PAM and OVA-peptide. After 4 days, splenocytes were isolated and analyzed by flow cytometry for CFSE-fluorescent signal of the infused cells. The cells shown are gated for the CD4+, Vα2+, CFSE+ cells, and propidium iodide–positive (death) cells were excluded from the analysis. The value indicates the percentage of cells within the proliferative fraction (>1 division). (B and C) TLR2 triggering abrogates Treg-mediated suppression of anti–C.albicans immunity in vivo. TLR2–/– mice (5 per group) were reconstituted with 4 × 106 WT PAM–expanded Tregs (B) or conventional Th cells (C) and challenged i.v. with 105 live C.albicans cells 1 day later (day 0). If indicated, mice received an i.p. injection of 100 μl saline (controls) or 20 μg PAM/100 μl saline on days –1, 1, 3, and 5. SEVEN days after the challenge, C.albicans outgrowth (CFU/g tissue ± SEM) from kidneys was monitored. (D) Ex vivo IFN-γ production (± SEM) by C.albicans–stimulated splenocytes was measured as described in Methods. Representative results of 2 independent experiments are shown. *P < 0.05 with TLR2–/– control.