title: Differential but direct abolishment of human regulatory T cell suppressive capacity by various TLR2 ligands.
abstract: CD4(+)CD25(high) regulatory T cells (Tregs) control cellular immune responses and maintain peripheral tolerance. We investigated whether TLR2 ligands are able to abrogate Treg-induced suppression in humans based on different reports about effects of triacylated lipopeptide Pam(3)CSK4 in mice. Pretreatment of human Tregs with a mixture of TLR2 ligands Pam(2)CSK4, FSL-1, and Pam(3)CSK4 reduced the Treg-mediated suppression of CD4(+)CD25(-) responder T cells in the majority of the analyzed donors. Differential effects of individual TLR2 ligands are explained by usage of different TLR2 heterodimers in the recognition of Pam(2)CSK4, FSL-1, and Pam(3)CSK4. In contrast to the murine system, TLR2 ligand-mediated abrogation of human Treg function was not associated with a downregulation of FoxP3 transcription factor. Furthermore, our results excluded an effect of TLR2 ligands on granzyme A/B release by human Tregs as a potential mechanism to abolish Treg-mediated suppression. Our data suggest that a downregulation of p27(Kip1) and restoration of Akt phosphorylation in human Tregs pretreated with TLR2 ligands result in a reversal of suppression on responder T cells. Moreover, our data indicate that a mixture of TLR2 ligands can be used to modulate human Treg activity.
authors.affiliation: Institute of Immunology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Hans-Heinrich
authors.initials: HH
authors.lastname: Oberg
authors.forename: Thi Thuy Hoa
authors.initials: TT
authors.lastname: Ly
authors.forename: Sandra
authors.initials: S
authors.lastname: Ussat
authors.forename: Tim
authors.initials: T
authors.lastname: Meyer
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
authors.forename: Daniela
authors.initials: D
authors.lastname: Wesch
mesh_terms: D000328:Adult; D002352:Carrier Proteins / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004075:Diglycerides / Q000378:metabolism / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D004338:Drug Combinations; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D055666:Lipopeptides / Q000378:metabolism / Q000494:pharmacology; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism* / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D004075:Diglycerides; D004338:Drug Combinations; C460864:FSL-1 lipoprotein, synthetic; D007166:Immunosuppressive Agents; D008024:Ligands; D055666:Lipopeptides; D009842:Oligopeptides; C499841:PAM2-Cys-SKKK; C508075:Pam(3)CSK(4) peptide; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2