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TLR2 Stimulation Regulates the Balance between Regulatory T Cell and Th17 Function: A Novel Mechanism of Reduced Regulatory T Cell Function in Multiple Sclerosis

Nyirenda, Mukanthu H.; Morandi, Elena; Vinkemeier, Uwe; Constantin-Teodosiu, Dumitru; Drinkwater, Sophie; Mee, Maureen; King, Lloyd; Podda, Giulio; Zhang, Guang-Xian; Ghaemmaghami, Amir; Constantinescu, Cris S.; Bar-Or, Amit; Gran, Bruno

Authors

Mukanthu H. Nyirenda

Elena Morandi

UWE VINKEMEIER uwe.vinkemeier@nottingham.ac.uk
Action Medical Research Professor of Cell Biology

Dumitru Constantin-Teodosiu

Sophie Drinkwater

Maureen Mee

Lloyd King

Giulio Podda

Guang-Xian Zhang

Cris S. Constantinescu

Amit Bar-Or

Bruno Gran



Abstract

CD4+CD25hi FOXP3+ regulatory T cells (Tregs) maintain tolerance to self-Ags. Their defective function is involved in the pathogenesis of multiple sclerosis (MS), an inflammatory demyelinating disease of the CNS. However, the mechanisms of such defective function are poorly understood. Recently, we reported that stimulation of TLR2, which is preferentially expressed by human Tregs, reduces their suppressive function and skews them into a Th17-like phenotype. In this study, we tested the hypothesis that TLR2 activation is involved in reduced Treg function in MS. We found that Tregs from MS patients expressed higher levels of TLR2 compared with healthy controls, and stimulation with the synthetic lipopeptide Pam3Cys, an agonist of TLR1/2, reduced Treg function and induced Th17 skewing in MS patient samples more than in healthy controls. These data provide a novel mechanism underlying diminished Treg function in MS. Infections that activate TLR2 in vivo (specifically through TLR1/2 heterodimers) could shift the Treg/Th17 balance toward a proinflammatory state in MS, thereby promoting disease activity and progression.

Journal Article Type Article
Publication Date Jun 15, 2015
Journal Journal of Immunology
Print ISSN 0022-1767
Electronic ISSN 1550-6606
Publisher American Association of Immunologists
Peer Reviewed Peer Reviewed
Volume 194
Issue 12
Pages 5761-5774
APA6 Citation Nyirenda, M. H., Morandi, E., Vinkemeier, U., Constantin-Teodosiu, D., Drinkwater, S., Mee, M., …Gran, B. (2015). TLR2 Stimulation Regulates the Balance between Regulatory T Cell and Th17 Function: A Novel Mechanism of Reduced Regulatory T Cell Function in Multiple Sclerosis. Journal of Immunology, 194(12), 5761-5774. https://doi.org/10.4049/%E2%80%8Bjimmunol.1400472
DOI https://doi.org/10.4049/%E2%80%8Bjimmunol.1400472
Publisher URL https://www.jimmunol.org/content/194/12/5761
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