CLCF1 promotes IL12Rβ2 proteolysis and limits Th1 differentiation.
Véronique Laplante1, Marine Rousseau2, Sarah Pasquin2
1Département de pharmacologie et physiologie, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
Cytokine
|July 8, 2025
Summary
Cardiotrophin-like cytokine factor 1 (CLCF1) negatively regulates Interleukin-12 (IL12) activity by promoting IL12 receptor degradation. This finding suggests CLCF1 as a therapeutic target for inflammatory Th1 cell responses.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Cardiotrophin-like cytokine factor 1 (CLCF1) is an IL6/IL12 family cytokine involved in immune modulation and motor neuron development.
- CLCF1's specific roles in immune cell regulation, particularly T cells, require further elucidation.
Purpose of the Study:
- To investigate the immune-modulating functions of CLCF1, focusing on its interaction with the IL12 signaling pathway.
- To characterize a novel mouse model lacking CLCF1 in hematopoietic cells.
Main Methods:
- Utilized a Vav-promoter driven Clcf1 knockout mouse model.
- Stimulated CD4+ T cells with IL12 and measured Interferon-gamma (IFNγ) production.
- Assessed IL12 receptor beta 2 (IL12Rβ2) expression levels and degradation pathways.
Main Results:
- Clcf1-deficient CD4+ T cells exhibited increased IFNγ production upon IL12 stimulation.
- CLCF1 was found to downregulate IL12Rβ2 expression.
- CLCF1 directly interacts with IL12Rβ2, promoting its proteasomal degradation independently of ubiquitination.
Conclusions:
- CLCF1 acts as a negative regulator of IL12 activity, impacting Th1 cell responses.
- CLCF1's role in mediating protein degradation may represent a novel biological function.
- CLCF1 presents a potential therapeutic target for modulating inflammatory conditions driven by Th1 cells.
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