TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes.
CD3-specific antibodies have the unique capacity to restore self-tolerance in established autoimmunity. They induce long-term remission of overt diabetes in nonobese diabetic (NOD) mice and in human type I diabetes. The underlying mechanisms had been unclear until now. Here we report that treatment with CD3epsilon-specific antibodies induces transferable T-cell-mediated tolerance involving CD4+CD25+ cells. However, these CD4+CD25+ T cells are distinct from naturally occurring regulatory T cells that control physiological autoreactivity. CD3-specific antibody treatment induced remission in NOD Cd28-/- mice that were devoid of such regulatory cells. Remission of diabetes was abrogated by coadministration of a neutralizing transforming growth factor (TGF)-beta-specific antibody. The central role of TGF-beta was further suggested by its increased, long-lasting production by CD4+ T cells from tolerant mice. These data explain the intriguing tolerogenic effect of CD3-specific antibodies and position them as the first clinically applicable pharmacological stimulant of TGF-beta-producing regulatory CD4+ T cells.
Belghith
Mériam
M
INSERM U580, IRNEM, Hôpital Necker, 161 Rue de Sèvres, 75015 Paris, France.
Bluestone
Jeffrey A
JA
Barriot
Samia
S
Mégret
Jérôme
J
Bach
Jean-François
JF
Chatenoud
Lucienne
L
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015375:Receptors, Interleukin-2 / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta