Innate CD4+CD25+ regulatory T cells are required for oral tolerance and inhibition of CD8+ T cells mediating skin inflammation.
To elucidate the role of CD4+CD25+ regulatory T cells in oral tolerance, we used the model of contact hypersensitivity (CHS) to 2,4-dinitrofluorobenzene (DNFB), which is mediated by CD8+ Tc1 effector cells independently of CD4+ T-cell help. Conversely to normal mice, invariant chain knock-out (KO) (Ii degrees / degrees ) mice, which are deficient in CD4+ T cells, cannot be orally tolerized and develop a chronic hapten-specific CHS response. Transfer of naive CD4+ T cells before hapten gavage into Ii degrees / degrees mice restores oral tolerance by a mechanism independent of interleukin-10 (IL-10) production by CD4+ T cells. That naturally occurring CD4+CD25+ T cells are critical for oral tolerance induction is demonstrated by the finding that (1) transfer of CD4+CD25+ but not CD4+CD25- T cells into Ii degrees / degrees recipients completely prevents the CHS response and skin infiltration by CD8+ T cells, by blocking development of hapten-specific CD8+ T cells; (2) in vivo depletion of CD4+CD25+ cells by antibody treatment in normal mice impairs oral tolerance; and (3) CD4+CD25+ T cells inhibit hapten-specific CD8+ T-cell proliferation and interferon gamma (IFN gamma) production, in vitro. These data show that naturally occurring CD4+CD25+ T cells are instrumental for orally induced tolerance and are key actors for the control of antigen-specific CD8+ T-cell effectors mediating skin inflammation.
Dubois
Bertrand
B
Department de Immunité, Institut National de la Santé et de la Recherche Médicale U404, Institut Fédératif de Recherche, 128 Bioscience Lyon Gerland, 21 avenue Tony Garnier, 69365 Lyon cedex 07, France.
Chapat
Ludivine
L
Goubier
Anne
A
Papiernik
Martine
M
Nicolas
Jean-François
JF
Kaiserlian
Dominique
D
D000284:Administration, Oral; D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003877:Dermatitis, Contact / Q000276:immunology*; D004139:Dinitrofluorobenzene / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D006241:Haptens / Q000008:administration & dosage / Q000276:immunology; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015375:Receptors, Interleukin-2
D006241:Haptens; D015375:Receptors, Interleukin-2; D004139:Dinitrofluorobenzene