IL-12 reverses established antigen-specific tolerance of contact sensitivity by affecting costimulatory molecules B7-1 (CD80) and B7-2 (CD86).
Cutaneous painting with reactive haptens induces contact sensitivity (CS) responses that are in vivo examples of T cell immunity. In contrast, high dose i.v. administration of the hapten can induce tolerance. We investigated the effect of IL-12 on reversal of this tolerance and attempted to determine in vitro the mechanism of this reversing effect by measuring proliferation and IFN-gamma production by CS effector T cells stimulated with hapten-conjugated APC, and we also measured CS ear swelling in vivo. The in vitro responses of T cells to hapten-APC became absent in tolerized mice, paralleling impaired in vivo CS responses. Addition of IL-12 to cultures manifesting this fully established in vitro tolerance completely restored impaired responses of tolerized T cells. The reversing effects of IL-12 were not blocked by anti-IFN-gamma mAb, but were blocked by mAbs against B7-1, more strongly by anti-B7-2, and by both Abs together. Additional in vivo ear-swelling response experiments confirmed the reversing effects of IL-12 on established tolerance. To examine whether the IL-12 effect depended on stimulation of IFN-gamma, we directly injected IFN-gamma into tolerized mice. This partially mimicked but did not fully reconstitute the effects of IL-12. In summary, IL-12 abrogation of established tolerance of CS may have been partially due to endogenous production of IFN-gamma, but appeared mainly due to direct activation of the tolerized T cells by affecting signaling through costimulatory molecules B7-1 and B7-2.
Ushio
H
H
Department of Veterinary Surgery, University of Osaka Prefecture College of Agriculture, Japan.
Tsuji
R F
RF
Szczepanik
M
M
Kawamoto
K
K
Matsuda
H
H
Askenase
P W
PW
D000818:Animals; D015703:Antigens, CD / Q000187:drug effects / Q000502:physiology*; D018122:B7-1 Antigen / Q000187:drug effects / Q000502:physiology*; D051940:B7-2 Antigen; D002478:Cells, Cultured; D003877:Dermatitis, Contact / Q000276:immunology*; D004487:Edema / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D006241:Haptens / Q000008:administration & dosage; D007108:Immune Tolerance / Q000187:drug effects*; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology; D018664:Interleukin-12 / Q000008:administration & dosage / Q000494:pharmacology*; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008808:Mice, Inbred CBA; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D000939:Epitopes; D006241:Haptens; D008562:Membrane Glycoproteins; D018664:Interleukin-12; D007371:Interferon-gamma