Cooperation of TLR12 and TLR11 in the IRF8-dependent IL-12 response to Toxoplasma gondii profilin.
TLRs play a central role in the innate recognition of pathogens and the activation of dendritic cells (DCs). In this study, we establish that, in addition to TLR11, TLR12 recognizes the profilin protein of the protozoan parasite Toxoplasma gondii and regulates IL-12 production by DCs in response to the parasite. Similar to TLR11, TLR12 is an endolysosomal innate immune receptor that colocalizes and interacts with UNC93B1. Biochemical experiments revealed that TLR11 and TLR12 directly bind to T. gondii profilin and are capable of forming a heterodimer complex. We also establish that the transcription factor IFN regulatory factor 8, not NF-κB, plays a central role in the regulation of the TLR11- and TLR12-dependent IL-12 response of DCs. These results suggest a central role for IFN regulatory factor 8-expressing CD8(+) DCs in governing the TLR11- and TLR12-mediated host defense against T. gondii.
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
Megan
M
Raetz
Alexey
A
Kibardin
Carolyn R
CR
Sturge
Reed
R
Pifer
Haiying
H
Li
Ezra
E
Burstein
Keiko
K
Ozato
Sergey
S
Larin
Felix
F
Yarovinsky
D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D016827:CD8 Antigens / Q000378:metabolism; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D051304:Profilins / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D014122:Toxoplasma / Q000276:immunology / Q000378:metabolism; D014124:Toxoplasmosis, Animal / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D000099185:Interferon Regulatory Factor-8
D000953:Antigens, Protozoan; D016827:CD8 Antigens; D050835:Interferon Regulatory Factors; D018664:Interleukin-12; D026901:Membrane Transport Proteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D051304:Profilins; D034741:RNA, Small Interfering; D051193:Toll-Like Receptors; D000099185:Interferon Regulatory Factor-8; C507780:Myd88 protein, mouse; C482903:Tlr11 protein, mouse; C539092:Tlr12 protein, mouse; C539093:Tlr13 protein, mouse; C512254:UNC93B1 protein, mouse