[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Laplante, Véronique; Département de pharmacologie et physiologie, Université de Montréal, Montréal, Québec H3T 1J4, Canada
Rousseau, Marine; 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
Pasquin, Sarah; 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
Bourel, Capucine; 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
Uriarte, Maxime ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques ; Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, Québec H1T 4B3, Canada
Affar, El Bachir; 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
Najmanovich, Rafael; Département de pharmacologie et physiologie, Université de Montréal, Montréal, Québec H3T 1J4, Canada
Lesage, Sylvie; 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
Gauchat, Jean-François; Département de pharmacologie et physiologie, Université de Montréal, Montréal, Québec H3T 1J4, Canada. Electronic address: jf.gauchat@umontreal.ca
Language :
English
Title :
CLCF1 promotes IL12Rβ2 proteolysis and limits Th1 differentiation.
Health Research Funds of Quebec CIHR - Canadian Institutes of Health Research UdeM - Université de Montréal
Funding text :
This work was supported by a grant from the Canadian Institutes of Health Research (CIHR; PTJ 159654) to Jean-Fran\u00E7ois Gauchat and Sylvie Lesage. V\u00E9ronique Laplante (FRQS - 319286) and Marine Rousseau (FRQS - 349187) are recipients from the Fond de Recherche du Qu\u00E9bec en Sant\u00E9, Capucine Bourel is a recipient from the Cole Foundation and the Cancer Research Society, and Sarah Pasquin is a recipient from the CIHR (Fellowship MFE 164666).We would like to thank the Institute for Research in Immunology and Cancer genomic platform for the sequencing and RT-qPCR experiments. We would also like to thank Armelle LeCampion (Flow cytometry core facility, Universit\u00E9 de Montr\u00E9al) for her support with our flow cytometry experiments, and Ernesto Fajardo (Lesage group) for his kind help with the management of our mouse colonies. We are grateful to Javier Marcelo Di Noia and Anne-Marie Patenaude (Montreal Clinical Research Institute, Montreal, QC) for their help and advice with the pMX retroviral vectors. Furthermore, we would like to thank Jean-Fran\u00E7ois Schmouth and his team at the CR-CHUM transgenic platform for their work in generating the Clcf1fl/fl mouse model. The graphical abstract for this article was created in BioRender (Laplante, V. (2025); https://BioRender.com/e3zojua).
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