title: Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype.
abstract: The immune system must distinguish not only between self and non-self, but also between innocuous and pathological foreign antigens to prevent unnecessary or self-destructive immune responses. Unresponsiveness to harmless antigens is established through central and peripheral processes. Whereas clonal deletion and anergy are mechanisms of peripheral tolerance, active suppression by T-regulatory 1 (Tr1) cells has emerged as an essential factor in the control of autoreactive cells. Tr1 cells are CD4+ T lymphocytes that are defined by their production of interleukin 10 (IL-10) and suppression of T-helper cells; however, the physiological conditions underlying Tr1 differentiation are unknown. Here we show that co-engagement of CD3 and the complement regulator CD46 in the presence of IL-2 induces a Tr1-specific cytokine phenotype in human CD4+ T cells. These CD3/CD46-stimulated IL-10-producing CD4+ cells proliferate strongly, suppress activation of bystander T cells and acquire a memory phenotype. Our findings identify an endogenous receptor-mediated event that drives Tr1 differentiation and suggest that the complement system has a previously unappreciated role in T-cell-mediated immunity and tolerance.
authors.affiliation: Division of Rheumatology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kemper
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Chan
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Green
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Brett
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology; D015847:Interleukin-4 / Q000378:metabolism; D008213:Lymphocyte Activation; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010641:Phenotype; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D017252:CD3 Complex; C497857:CD46 protein, human; D007376:Interleukin-2; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma