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Essential Role of T Cell NF-B Activation in Collagen-Induced Arthritis¹

Rajalakshmi Seetharaman^*, Ana L. Mora, Gerald Nabozny, Mark Boothby and Jin Chen^2,*

Departments of ^* Medicine/Rheumatology and Cell Biology and Microbiology and Immunology, Vanderbilt University, Nashville, TN 37232; and Department of Pharmacology, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT 06877

NF-B/Rel proteins are ubiquitous transcription factors that are activated by proinflammatory signals or engagement of Ag receptors. To study the role of NF-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-B/Rel (IB(N)) in the T lineage. Expression of the IB(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 IB(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- production in vivo. Consistent with decreased level of anti-type II collagen-specific Abs and IFN-, 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-B in T cells impairs CIA development in vivo through decreases in type 1 T cell-dependent responses.

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