CLCF1 promotes IL12Rβ2 proteolysis and limits Th1 differentiation

Cardiotrophin-like cytokine factor 1 (CLCF1) is a cytokine of the IL6/IL12 family with immune-modulating functions, mainly on B cells and myeloid cells. CLCF1 also plays a crucial role in the embryonic development of motor neurons, such that Clcf1-knock out mice are not viable. In order to further study the immune activities of CLCF1, we used a mouse model with a knock-out of Clcf1 in hematopoietic cells under the Vav promoter. While characterizing this model, we observed that CD4⁺ T cells from Clcf1^-/- mice produced more IFNγ than those from Clcf1^+/+ mice when activated in the presence of IL12. We also observed that CLCF1 induces a downregulation of IL12Rβ2 expression levels. We further demonstrated that CLCF1 interacts with IL12Rβ2 and promotes its degradation through the proteasome in a manner independent of ubiquitination. Altogether, these results suggest that CLCF1 can act as a negative regulator of IL12 activity, a role which could be exploited therapeutically to dampen the inflammatory response driven by Th1 cells. Our observations may also hint at a new role for CLCF1 as a mediator of protein degradation.