title: Complement regulates conventional DC-mediated NK-cell activation by inducing TGF-β1 in Gr-1+ myeloid cells.
abstract: Complement activation modulates DC-mediated T-cell activation, but whether complement affects DC-mediated priming of NK cells is unknown. Here, we demonstrated that conventional DCs (cDCs) from C3(-/-)  and C5aR(-/-)  mice are hyperresponsive to polyI:C, a TLR3 ligand, leading to enhanced NK-cell activation. We found that cDCs lack C5a receptor (C5aR) and do not respond to C5a directly. Depletion of Gr-1(+)  myeloid cells augments polyI:C-induced cDC activation in WT but not in C3(-/-)  or C5aR(-/-)  mice, indicating that the effect of complement activation on cDCs is indirectly mediated through C5aR-expressing Gr-1(+)  myeloid cells. We further demonstrated that the mechanism by which Gr-1(+)  myeloid cells regulate the activity of cDCs involves C5a-dependent TGF-β1 production in Gr-1(+)  myeloid cells. C5a enhances and blocking C5aR decreases TGF-β1 production in cultured bone marrow Gr-1(+) CD11b(+)  cells. C5aR deficiency is associated with reduced circulating TGF-β1 levels, while depleting Gr-1(+)  myeloid cells abrogates this difference between WT and C5aR(-/-)  mice. Lastly, we showed that enhanced cDC-NK-cell activity in C3(-/-)  mice led to delayed melanoma tumor growth. Thus, complement activation indirectly regulates cDC-NK-cell activation in response to inflammatory stimuli such as TLR3 by promoting TGF-β1 production in Gr-1(+)  myeloid cells at steady state.
authors.affiliation: Program in Inflammation and Autoimmunity, Hospital for Special Surgery, New York, NY, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Qing
authors.forename: Gloria C
authors.initials: GC
authors.lastname: Koo
authors.forename: Jane E
authors.initials: JE
authors.lastname: Salmon
mesh_terms: D000818:Animals; D003176:Complement C3 / Q000172:deficiency / Q000276:immunology; D015936:Complement C5a / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology*; D011070:Poly I-C / Q000276:immunology / Q000494:pharmacology; D044087:Receptor, Anaphylatoxin C5a / Q000276:immunology*; D019707:Receptors, Chemokine / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000276:immunology*
chemical_list: D003176:Complement C3; C503133:Gr-1 protein, mouse; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D053773:Transforming Growth Factor beta1; D015936:Complement C5a; D011070:Poly I-C