Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells.
Toll-like receptors (TLRs) are primary sensors of both innate and adaptive immune systems and play a pivotal role in response against structurally conserved components of pathogens. Synthetic bacterial lipoprotein (BLP) Pam3Cys-SK4 is a TLR2 agonist that is capable of modulating T cell immune responses. We show here that BLP, together with anti-CD3 antibody [T cell receptor (TcR) activation], induced proliferation of both CD4+ CD25+ regulatory T cells (Tregs) and CD4+ CD25- (effector) T cells in the absence of antigen-presenting cells. The expanded Tregs showed a transient loss of suppressive activity. Moreover, BLP rendered effectors resistant to the suppression of Tregs by increasing IL-2 secretion. BLP also transiently suppressed the induction of Foxp3 (X-linked forkhead/winged helix transcription factor) mRNA in Tregs at the first 8-15 h after T cell receptor activation. Consistent with this observation, BLP-stimulated Tregs regained their inhibitory activity and prevented spontaneous colitis induced by effectors in severe combined immunodeficient mice. Our results demonstrate a previously unrecognized pathway by which TLR expressed on T cells may directly modulate the immune response. Thus, during an acute bacterial infection, BLP may rapidly increase the host's adaptive immunity by expanding effectors and also by attenuating the suppressive activity of Tregs. In the process, BLP also expands the Tregs, which recover their suppressive activity when the infection has subsided, in time to limit potential autoimmunity that might result from the overactivated effectors.
Liu
Haiying
H
Division of Immunology, Infection, and Inflammation, University of Glasgow, Glasgow G11 6NT, United Kingdom.
Komai-Koma
Mousa
M
Xu
Damo
D
Liew
Foo Y
FY
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006706:Homeostasis; D007376:Interleukin-2 / Q000276:immunology; D055666:Lipopeptides; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D010455:Peptides / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D015398:Signal Transduction / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000276:immunology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D010455:Peptides; D015375:Receptors, Interleukin-2; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2