The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies

Abstract

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 (h 2 =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 underrepresented 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.

Evolving Identification of Blood Cells Associated with Clinically Isolated Syndrome: Importance of Time since Clinical Presentation and Diagnostic MRI

“…This finding was reinforced by the negative correlation between CD56bright NK cell frequencies and time since MRI across all CIS blood samples. Our results support previous findings that peripheral blood from people with MS has fewer CD56bright NK cells than HC [4]. Other findings have been reported; CD56bright NK cells were increased in blood from people with RRMS with no disease-associated MRI changes over 2.4 years [5].…”

T-bet and Eomesodermin in NK Cell Development, Maturation, and Function

“…This hypothesis is supported by a recent study showing that adoptively transferred IL-12/15/18-preactivated NK cells, which do not undergo exhaustion and maintain high levels of Eomes and T-bet expression, suppressed acute Graft-versus-Host-Disease in a murine model of HSCT ( 47 ). These results suggest that T-bet and Eomes expression may also modulate NK cell function in immunopathological settings, similarly to what recently shown in multiple sclerosis patients ( 35 ).…”

“…Similar patterns of T-bet and Eomes expression exist in human NK cells that also upregulate T-bet and downregulate Eomes during peripheral maturation (Figure 2 ). Cytokine-producing CD56 bright NK cells express higher levels of Eomes and lower levels of T-bet than cytotoxic CD56 dim NK cells ( 10 – 12 , 34 , 35 ). Moreover, terminally differentiated CD57 pos CD56 dim NK cells express the highest levels of T-bet and the lowest levels of Eomes ( 11 , 12 ).…”

The Multiple Sclerosis (MS) Genetic Risk Factors Indicate both Acquired and Innate Immune Cell Subsets Contribute to MS Pathogenesis and Identify Novel Therapeutic Opportunities

“…Differences in differentiation of immune cells between individuals are controlled by genetic variation, e.g., of transcription factors, cytokine receptors, and signaling molecules. MS risk genes such as TYK2 (28, 29), IL2Ra (30), EOMES (31), NFKB1 (32), and ZMIZ1 (33) are associated with immune cell population differences in MS. Increased understanding of immune dysregulation in MS, the nature of control of this dysregulation, and identification of points for therapeutic intervention will come from further investigation of how risk genes and alleles affect heritable immune cell populations.…”