IL-12 Reverses Established Antigen-Specific Tolerance of Contact Sensitivity by Affecting Costimulatory Molecules B7-1 (CD80) and B7-2 (CD86)

• Published in: The Journal of immunology (1950) Vol. 160; no. 5; pp. 2080 - 2088
• Main Authors: Ushio, Hiroko, Tsuji, Ryohei F, Szczepanik, Marian, Kawamoto, Keiko, Matsuda, Hiroshi, Askenase, Philip W
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.03.1998
• Subjects: Animals; Antigens, CD - drug effects; Antigens, CD - physiology; B7-1 Antigen - drug effects; B7-1 Antigen - physiology; B7-2 Antigen; Cells, Cultured; Dermatitis, Contact - immunology; Edema - immunology; Epitopes - immunology; Haptens - administration & dosage; Immune Tolerance - drug effects; Injections, Intravenous; Interferon-gamma - biosynthesis; Interferon-gamma - physiology; Interleukin-12 - administration & dosage; Interleukin-12 - pharmacology; Lymph Nodes - cytology; Lymphocyte Activation - drug effects; Male; Membrane Glycoproteins - drug effects; Membrane Glycoproteins - physiology; Mice; Mice, Inbred CBA; T-Lymphocytes - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.160.5.2080

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.