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).

Credit: Springer Nature Limited

“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.