title: Complement promotes the development of inflammatory T-helper 17 cells through synergistic interaction with Toll-like receptor signaling and interleukin-6 production.
abstract: Toll-like receptors (TLRs) and complement are 2 major components of innate immunity that provide a first-line host defense and shape the adaptive immune responses. We show here that coincidental activation of complement and several TLRs in mice led to the synergistic production of serum factors that promoted T-helper cell 17 (Th17) differentiation from anti-CD3/CD28 or antigen-stimulated T cells. Although multiple TLR-triggered cytokines were regulated by complement, Th17 cell-promoting activity in the serum was correlated with interleukin (IL)-6 induction, and antibody neutralization of IL-6 abrogated the complement effect. By using both in vitro and in vivo approaches, we examined in more detail the mechanism and physiologic implication of complement/TLR4 interaction on Th17-cell differentiation. We found that the complement effect required C5a receptor, was evident at physiologically relevant levels of C5a, and could be demonstrated in cultured peritoneal macrophages as well as in the setting of antigen immunization. Importantly, despite an inhibitory effect of complement on IL-23 production, complement-promoted Th17 cells were functionally competent in causing autoimmunity in an adoptive transfer model of experimental autoimmune encephalomyelitis. Collectively, these data establish a link between complement/TLR interaction and Th17-cell differentiation and provide new insight into the mechanism of action of complement in autoimmunity.
authors.affiliation: Institute for Translational Medicine and Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Chongyun
authors.initials: C
authors.lastname: Fang
authors.forename: Xinhua
authors.initials: X
authors.lastname: Zhang
authors.forename: Takashi
authors.initials: T
authors.lastname: Miwa
authors.forename: Wen-Chao
authors.initials: WC
authors.lastname: Song
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018958:CD55 Antigens / Q000235:genetics; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D003167:Complement Activation; D015936:Complement C5a / Q000502:physiology / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology; D007113:Immunity, Innate; D007114:Immunization; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D038041:Lymphopoiesis; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044087:Receptor, Anaphylatoxin C5a / Q000172:deficiency / Q000502:physiology; D011994:Recombinant Proteins / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D006377:T-Lymphocytes, Helper-Inducer / Q000145:classification / Q000166:cytology* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology*
chemical_list: D018958:CD55 Antigens; D016207:Cytokines; D015850:Interleukin-6; D044087:Receptor, Anaphylatoxin C5a; D011994:Recombinant Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015936:Complement C5a