PT  - JOURNAL ARTICLE
AU  - Wanhu Tang
AU  - Hongshan Wang
AU  - Philip M. Murphy
AU  - Ulrich Siebenlist
TI  - Bcl-3 suppresses Th9 differentiation by regulating glutamine utilization
AID  - 10.1101/2021.07.06.451316
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.07.06.451316
4099  - http://biorxiv.org/content/early/2021/07/08/2021.07.06.451316.short
4100  - http://biorxiv.org/content/early/2021/07/08/2021.07.06.451316.full
AB  - Bcl-3 is an atypical member of the IκB protein family that plays important and diverse roles in both innate and adaptive immunity, including Th17-dependent autoimmunity models in mice. When naïve mouse splenic CD4+ T cells were cultured under Th17 conditions in vitro, we unexpectedly found that the most highly differentially expressed gene between wild type and Bcl-3-deficient (KO) Th17 cells encoded the cytokine IL-9. We therefore investigated the role of Bcl-3 in Th9 cell differentiation. When naïve CD4+ T cells were cultured under Th9-polarizing conditions in vitro, the extent of Th9 differentiation observed in wild type cells was increased in Bcl-3 KO cells and conversely was decreased in cells overexpressing Bcl-3. The suppressive effect of Bcl-3 on Th9 differentiation was cell-autonomous, and NF-κB inhibitors abolished increased Th9 differentiation in Bcl-3 KO cells. Consistent with this, in the Th9 transfer model of OVA-induced allergic airway inflammation, mice receiving Bcl-3 KO cells had greater immune cell infiltration in the lung than mice receiving wild type cells.Mechanistically, unsupervised transcriptomic analysis revealed differentially expressed genes in KO cells, including the glutamine transporter Slc1a5, which was downregulated. The functional significance of this was suggested by the ability of increasing concentrations of glutamine in the media to reduce the difference in Th9 differentiation between WT and KO cells. Our results suggest a novel role for Bcl-3 as a negative regulator of Th9 differentiation, in part by limiting glutamine accessibility through downregulation of Slc1a5.Competing Interest StatementThe authors have declared no competing interest.