New research published in Nature Communications identifies a regulatory mechanism to account for the switching of IFNγ production to IL-10 production by T cells, a step that is thought to be important to limit inflammation and the progression of inflammatory diseases such as rheumatoid arthritis (RA).
“We tried to better understand which signals regulate this switch,” explains Esperanza Perucha, co-corresponding author of the new study. “We discovered that cholesterol homeostasis regulates IL-10 expression in human CD4+ T cells.”
To mimic switching in vitro, the researchers stimulated T cells with anti-CD3 and anti-CD46 antibodies, a culture condition that initially results in IFNγ and IL-2 production. Accumulation of IL-2 in such cultures then prompts IFNγ+ T cells to produce IL-10, and then in a final phase these cells are fully switched and produce IL-10, but not IFNγ.
By comparing gene expression of cells from each of these three stages of the culture and then running pathway analyses, the researchers found a strong association between the cholesterol biosynthesis pathway and the licensing of IFNγ+ T cells to switch to IL-10 production.
To functionally validate this finding, the researchers inhibited cholesterol biosynthesis in vitro with the synthetic statin atorvastatin, which prevented IFNγ+ T cells from producing IL-10. A similar block to switching was noted when the cultures were treated with the cholesterol derivative 25-hydroxycholesterol (25-HC), and 25-HC was shown to reduce expression of c-Maf, the master transcription factor of IL-10 production.
“These findings provide a molecular framework for the so-called ‘lipid paradox’, in which high levels of systemic cholesterol have been linked to remission in RA,” says Andrew Cope, co-corresponding author of the study.
25-HC was shown to reduce expression of c-Maf
As preliminary evidence, the researchers also show a positive association between expression of CH25H (which encodes the enzyme that converts cholesterol to 25-HC) and progression to RA in a small cohort of patients with autoantibody-positive arthralgia.
References
Original article
Perucha, E. et al. The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells. Nat. Commun. 10, 498 (2019)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bernard, N.J. Cholesterol test for T cells. Nat Rev Rheumatol 15, 189 (2019). https://doi.org/10.1038/s41584-019-0195-9
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41584-019-0195-9