2. Academic Validation
  3. CLCF1 promotes IL12Rβ2 proteolysis and limits Th1 differentiation

CLCF1 promotes IL12Rβ2 proteolysis and limits Th1 differentiation

  • Cytokine. 2025 Oct:194:156989. doi: 10.1016/j.cyto.2025.156989.
Véronique Laplante 1,  Marine Rousseau 2,  Sarah Pasquin 2,  Capucine Bourel 2,  Maxime Uriarte 3,  El Bachir Affar 4,  Rafael Najmanovich 1,  Sylvie Lesage 2,  Jean-François Gauchat 5
Affiliations

Affiliations

  • 1 Département de pharmacologie et physiologie, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
  • 2 Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, Québec H3T 1J4, Canada; Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, Québec H1T 4B3, Canada.
  • 3 Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, Québec H1T 4B3, Canada.
  • 4 Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, Québec H1T 4B3, Canada; Département de médecine, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
  • 5 Département de pharmacologie et physiologie, Université de Montréal, Montréal, Québec H3T 1J4, Canada. Electronic address: jf.gauchat@umontreal.ca.
PMID: 40628045 DOI: 10.1016/j.cyto.2025.156989
Abstract

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.

Keywords

Cardiotrophin-like cytokine factor 1; Cytokine-receptor interaction; IL12; IL12Rβ2; Proteolysis; Th1 cells.

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