Induction and prevention of colonic inflammation in IL-2-deficient mice.
Gene-targeted mice deficient for IL-2 (IL-2 -/- mice) are free of apparent disease when maintained under germfree conditions but develop colitis and autoimmunity in a conventional environment. Here we show that colitis can be reproducibly induced in IL-2 -/- mice, but not in IL-2 +/+ mice, by i.p. immunization with Ag in CFA; thus enabling the systematic study of the immunopathogenesis of the colitis. We found that TNP-KLH or TNP-OVA had the most significant effect in inducing colitis, and while TNP-KLH immunization leads to the early appearance of activated T cells in the colons of both IL-2 -/- and IL-2 +/+ mice, only lamina propria cells of IL-2 -/- mice produced high amounts of INF-gamma. Moreover, both infiltrating colon CD4+ (69%) and CD8+ (6%) T cells secrete large amounts of IFN-gamma; however, only the depletion of CD4+ T cells leads to abrogation of the inflammation. In further analysis, we showed that the high IFN-gamma production is IL-12 driven, since colonic tissues of IL-2 -/- mice but not IL-2 +/+ mice show the presence of heterodimeric IL-12 and co-administration of anti-IL-12 with TNP-KLH completely prevented colitis and significantly reduced IFN-gamma production. Finally, we demonstrate that IL-2 -/- mice are deficient in their ability to induce Th2 responses after TNP-KLH challenge and that such immunization also leads to autoimmune-like phenomena in other organs of IL-2 -/- mice. These findings suggest that in the absence of IL-2 systemic administration of Ag induces primarily Th1 cells driven by overexpression of heterodimeric IL-12.
Ehrhardt
R O
RO
Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institutes of Health, Bethesda, MD 20892, USA.
Lúdvíksson
B R
BR
Gray
B
B
Neurath
M
M
Strober
W
W
D000818:Animals; D000955:Antigens, T-Independent / Q000276:immunology; D003092:Colitis / Q000139:chemically induced* / Q000276:immunology / Q000517:prevention & control*; D006241:Haptens / Q000276:immunology; D006433:Hemocyanins / Q000633:toxicity; D007114:Immunization; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis / Q000633:toxicity; D018664:Interleukin-12 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000172:deficiency* / Q000235:genetics*; D015847:Interleukin-4 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D010047:Ovalbumin / Q000276:immunology / Q000633:toxicity; D013601:T-Lymphocytes / Q000378:metabolism; D014301:Trinitrobenzenes / Q000276:immunology* / Q000633:toxicity*
D000955:Antigens, T-Independent; D006241:Haptens; D007376:Interleukin-2; D014301:Trinitrobenzenes; C054401:trinitrophenyl keyhole limpet hemocyanin; C038600:trinitrophenyl-ovalbumin; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D010047:Ovalbumin; D006433:Hemocyanins