The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56Â + cell dysregulation and is affected by immunomodulatory therapies

•Expression of EOMES and TBX21 is low in blood from MS patients, and longitudinally stable.•EOMES-TBX21 (“ET”) molecular phenotype is heritable and affected by MS therapies.•A subset of immune cells in the blood is tagged by expression of EOMES and TBX21 in MS and controls.•ET phenotype may be useful as a biomarker of clinical response to MS therapies.

Multiple Sclerosis (MS) is an autoimmune disease treated by therapies targeting peripheral blood cells. We previously identified that expression of two MS-risk genes, the transcription factors EOMES and TBX21 (ET), was low in blood from MS and stable over time. Here we replicated the low ET expression in a new MS cohort (p < 0.0007 for EOMES, p < 0.028 for TBX21) and demonstrate longitudinal stability (p < 10− 4) and high heritability (h2 = 0.48 for EOMES) for this molecular phenotype. Genes whose expression correlated with ET, especially those controlling cell migration, further defined the phenotype. CD56 + cells and other subsets expressed lower levels of Eomes or T-bet protein and/or were under-represented in MS. EOMES and TBX21 risk SNP genotypes, and serum EBNA-1 titres were not correlated with ET expression, but HLA-DRB1*1501 genotype was. ET expression was normalised to healthy control levels with natalizumab, and was highly variable for glatiramer acetate, fingolimod, interferon-beta, dimethyl fumarate.