The Oncoprotein and Transcriptional Regulator Bcl-3 Governs Plasticity and Pathogenicity of Autoimmune T Cells

• Bcl-3 prevents conversion of autoimmune Th1 to Th17 cells in vitro and in vivo
• Bcl-3 controls GM-CSF production and Th1 cell pathogenicity
• Bcl-3 binds to RORc promoter and regulates Th1 cell plasticity via RORγt

SummaryBcl-3 is an atypical member of the IκB family that modulates transcription in the nucleus via association with p50 (NF-κB1) or p52 (NF-κB2) homodimers. Despite evidence attesting to the overall physiologic importance of Bcl-3, little is known about its cell-specific functions or mechanisms. Here we demonstrate a T-cell-intrinsic function of Bcl-3 in autoimmunity. Bcl-3-deficient T cells failed to induce disease in T cell transfer-induced colitis and experimental autoimmune encephalomyelitis. The protection against disease correlated with a decrease in Th1 cells that produced the cytokines IFN-γ and GM-CSF and an increase in Th17 cells. Although differentiation into Th1 cells was not impaired in the absence of Bcl-3, differentiated Th1 cells converted to less-pathogenic Th17-like cells, in part via mechanisms involving expression of the RORγt transcription factor. Thus, Bcl-3 constrained Th1 cell plasticity and promoted pathogenicity by blocking conversion to Th17-like cells, revealing a unique type of regulation that shapes adaptive immunity.

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