Pathogenic responses of the TH17 subset of helper T cells are associated with disease flares in patients with multiple sclerosis, who also show unexplained seasonal variation in relapses. In Cell, Farez et al. report that melantonin interferes with expression of the transcription factor RORγt, a key driver of the polarization and effector function of TH17 cells. The concentration of melatonin in serum is inversely correlated with the abundance of TH17 cells and multiple sclerosis flares, which suggests a possible role for melatonin in this seasonal variation. Melatonin signaling activates an Erk kinase–expression pathway that relieves inhibition of expression of the transcription factor NFIL3, which itself inhibits expression of the gene encoding RORγt. Mice lacking expression of melatonin receptors fail to repress TH17 differentiation. Melatonin also enhances interleukin 10 expression to induce type 1 regulatory T cells. Thus, seasonal variation in melatonin expression alters the balance between these cell populations and thereby alters the pathogenic immune responses associated with multiple sclerosis flares.

Cell 162, 1338–1352 (2015)