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