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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 Article has an altmetric score of 3

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

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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 5

Proliferation of PAM-expanded Tregs.

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Proliferation of PAM-expanded Tregs.
(A) TLR2 and TCR signals cooperate ...
(A) TLR2 and TCR signals cooperate to increase CD25 expression on Tregs. Tregs were incubated with either PAM, anti-CD3, or a combination of both in IL-2–supplemented medium. CD25 expression was analyzed daily by flow cytometry and indicated as MFI relative to the medium control. (B) Proliferation of Tregs is induced by TLR2 signaling. PAM-cultured Tregs were stimulated on anti-CD3–coated plates with IL-2 (medium control) or with addition of the indicated TLR ligands. After 3 days, proliferation was measured by [3H]thymidine incorporation and shown as average cpm of triplicates relative to medium control ± SD. (C) Proliferation of CFSE-labeled PAM-expanded Tregs. The labeled Tregs were cultured for 3 days in the presence of IL-2–supplemented medium or with the indicated stimulus (PAM and/or anti-CD3). Proliferation resulting in a decrease of fluorescent signal in the daughter cells was monitored by flow cytometry and (since in vitro–cultured T cell lines display a more broad signal after CFSE labeling compared with freshly isolated T cells) analyzed using ModFit software. Representative results from 3 experiments are shown.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 6 patents
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