Essential role of T cell NF-kappa B activation in collagen-induced arthritis.
NF-kappa B/Rel proteins are ubiquitous transcription factors that are activated by proinflammatory signals or engagement of Ag receptors. To study the role of NF-kappa B/Rel signaling in T lymphocytes during autoimmune disease, we investigated type II collagen-induced arthritis (CIA) in transgenic mice expressing a constitutive inhibitor of NF-kappa B/Rel (I kappa B alpha(Delta N)) in the T lineage. Expression of the I kappa B alpha(Delta N) transgene was persistently high in adult peripheral lymphoid organs and undetectable in T cell-depleted splenocytes, suggesting the expression of the transgene is restricted to the T lineage. The incidence and severity of CIA were decreased significantly in these I kappa B alpha(Delta N) transgenic mice compared with nontransgenic littermates. Inhibition of CIA was not due solely to a decrease in their CD8+ population because transfer of wild-type CD8+ cells into transgenic mice failed to restore disease susceptibility. Protection against disease was associated with a moderate decrease in clonal expansion and a profound and persistent decrease in Ag-induced IFN-gamma production in vivo. Consistent with decreased level of anti-type II collagen-specific Abs and IFN-gamma, serum levels of IgG2a anti-CII Abs were significantly reduced. However, anti-CII-specific IgG1 levels were normal, indicating that some aspects of T cell help were unaffected. Taken together, these results suggest that inhibition of NF-kappa B in T cells impairs CIA development in vivo through decreases in type 1 T cell-dependent responses.
Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
R
R
Seetharaman
A L
AL
Mora
G
G
Nabozny
M
M
Boothby
J
J
Chen
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology / Q000637:transplantation; D002417:Cattle; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D003094:Collagen / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D020672:I-kappa B Proteins; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D015994:Incidence; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018655:Lymphocyte Count; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D019076:Transgenes / Q000276:immunology
D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D020672:I-kappa B Proteins; D007074:Immunoglobulin G; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D007371:Interferon-gamma; D003094:Collagen