title: Human complement C3 deficiency: Th1 induction requires T cell-derived complement C3a and CD46 activation.
abstract: Human T helper type 1 (Th1) responses are essential in defense. Although T cell receptor (TCR) and co-stimulator engagement are indispensable for T cell activation, stimulation of additional receptor pathways are also necessary for effector induction. For example, engagement of the complement regulator CD46 by its ligand C3b generated upon TCR activation is required for IFN-γ production as CD46-deficient patients lack Th1 responses. Utilizing T cells from two C3-deficient patients we demonstrate here that normal Th1 responses also depend on signals mediated by the anaphylatoxin C3a receptor (C3aR). Importantly, and like in CD46-deficient patients, whilst Th1 induction are impaired in C3-deficient patients in vitro, their Th2 responses are unaffected. Furthermore, C3-deficient CD4(+) T cells present with reduced expression of CD25 and CD122, further substantiating the growing notion that complement fragments regulate interleukin-2 receptor (IL-2R) assembly and that disturbance of complement-guided IL-2R assembly contributes to aberrant Th1 effector responses. Lastly, sustained intrinsic production of complement fragments may participate in the Th1 contraction phase as both C3a and CD46 engagement regulate IL-10 co-expression in Th1 cells. These data suggest that C3aR and CD46 activation via intrinsic generation of their respective ligands is an integral part of human Th1 (but not Th2) immunity.
authors: Université Joseph Fourier, GREPI/AGIM CNRS FRE3405, Grenoble, France.
authors: Arije
authors: A
authors: Ghannam
authors: Pédiatrie, CHU de Clermont-Ferrand, Clermont-Ferrand, France.
authors: Jean-Luc
authors: JL
authors: Fauquert
authors: Oncologie pédiatrique, CHU de Nantes, Nantes, France.
authors: Caroline
authors: C
authors: Thomas
authors: Division of Transplantation Immunology and Mucosal Biology (DTIMB), MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors: Claudia
authors: C
authors: Kemper
authors: Université Joseph Fourier, GREPI/AGIM CNRS FRE3405, Grenoble, France. Electronic address: christian.drouet@ujf-grenoble.fr.
authors: Christian
authors: C
authors: Drouet
mesh_terms: D003176:Complement C3 / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D053646:Interleukin-2 Receptor beta Subunit / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051916:Membrane Cofactor Protein / Q000276:immunology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011951:Receptors, Complement / Q000235:genetics / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
chemical_list: D003176:Complement C3; C508609:IL10 protein, human; C508594:IL2 protein, human; C508598:IL4 protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D053646:Interleukin-2 Receptor beta Subunit; D051916:Membrane Cofactor Protein; D034741:RNA, Small Interfering; D011951:Receptors, Complement; D015375:Receptors, Interleukin-2; C085567:complement C3a receptor; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma
keywords: C3 deficiency; C3a; Complement; T cell effector response