Toll-like receptor 2 controls expansion and function of regulatory T cells.
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 CD4CD25 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.
Sutmuller
Roger P M
RP
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
den Brok
Martijn H M G M
MH
Kramer
Matthijs
M
Bennink
Erik J
EJ
Toonen
Liza W J
LW
Kullberg
Bart-Jan
BJ
Joosten
Leo A
LA
Akira
Shizuo
S
Netea
Mihai G
MG
Adema
Gosse J
GJ
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D002177:Candidiasis / Q000276:immunology; D003545:Cysteine / Q000031:analogs & derivatives / Q000276:immunology; D008074:Lipoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*; D019076:Transgenes
D048868:Adaptor Proteins, Signal Transducing; D015704:CD4 Antigens; D008074:Lipoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C069172:2,3-bis(palmitoyloxy)-2-propyl-1-palmitoylcysteine; D003545:Cysteine