IL-12 prevents tolerance induction with mouse thyroglobulin by priming pathogenic T cells in experimental autoimmune thyroiditis: role of IFN-gamma and the costimulatory molecules CD40l and CD28.
Deaggregated mouse thyroglobulin (dMTg) induces tolerance to experimental autoimmune thyroiditis (EAT), a Th1-cell-mediated disease. To test whether IL-12, a potent activator of Th1 cells, can overcome tolerance induction, different doses of IL-12 were given to CBA/J mice during the critical interval of 2--3 days after dMTg administration. After challenge with MTg/LPS, dMTg/IL-12-pretreated mice showed more extensive thyroiditis than immunized controls, but comparable levels of anti-MTg and T cell proliferation. Without challenge, few MTg antibodies were produced. In contrast, pretreatment with dMTg/poly A:U or dMTg/IL-1, two other T cell activators which also interfere with tolerance induction, induced antibodies before challenge, but not more severe thyroiditis. Mice pretreated with IL-12 without dMTg developed thyroiditis comparable to immunized controls, but less severe thyroiditis than dMTg/IL-12-pretreated mice. Clearly, IL-12 not only blocked tolerance induction, but also primed antigen-specific T cells during the tolerogenic period of dMTg pretreatment, resulting in stronger thyroiditis than immunization only. Neither treatment with anti-IFN-gamma nor the use of IFN-gamma knockout mice altered the capacity of IL-12 to prevent tolerance induction. However, both anti-CD28 and anti-CD40L antibodies diminished the priming effect by dMTg/IL-12. The mechanisms of IL-12 action include priming of MTg-specific T cells and the involvement of T cell costimulatory molecules.
Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
W
W
Zhang
J C
JC
Flynn
Y C
YC
Kong
D000818:Animals; D018106:CD28 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D017353:Gene Deletion; D007108:Immune Tolerance / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D007132:Immunoglobulin Isotypes / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D018664:Interleukin-12 / Q000008:administration & dosage / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D013954:Thyroglobulin / Q000008:administration & dosage / Q000276:immunology*; D013967:Thyroiditis, Autoimmune / Q000276:immunology* / Q000473:pathology
D018106:CD28 Antigens; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D008070:Lipopolysaccharides; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma; D013954:Thyroglobulin