T_H1 identity

Bcl-3 is an inhibitor of transcription factor NF-κB (IκB) family protein that associates with DNA-bound homodimers of the NF-κB subunits p50 and p52 and can either promote NF-κB-dependent gene expression or inhibit it. In Immunity, Siebenlist and colleagues show that Bcl-3 serves as a regulator of the T_H1 lineage identity by preventing conversion into T_H17 cells. In a model of colitis in mice deficient in recombination-activating gene 1 (Rag1^−/− mice), transferred Bcl3^−/− CD4⁺T cells do not induce inflammation. Naive Bcl3^−/− CD4⁺ T cells differentiate normally into T_H1 cells in vitro and in vivo, but trace experiments with interferon-γ (IFN-γ) tagged with yellow fluorescent protein show that they gradually and cell-autonomously convert into IFN-γ⁺IL-17⁺ T cells and later into IL-17⁺ T cells in the mesenteric lymph nodes of Rag1^−/− hosts after transfer. The process is dependent on microbiota, stimulation via the T cell antigen receptor and IL-23. In T_H1 cells, Bcl-3 associates with the NF-κB subunits c-Rel and p50 in the promoter of the gene encoding the transcription factor RORγt. Expression of RORγt is higher in Bcl-3-deficient T_H1 cells, which is sufficient to induce conversion into T_H17 cells.

Immunity 41, 555–566 (2014)