TBX21 and HLX1 Polymorphisms Influence Cytokine Secretion at Birth

Abstract

BackgroundTBX21 (T cell specific T-box transcription factor) and HLX1 (H.20-like homeobox 1) are crucial transcription factors of TH1-cells, inducing their differentiation and suppressing TH2 commitment, particularly important for early life immune development. This study investigated the influence of TBX21 and HLX1 single nucleotide polymorphisms (SNPs), which have previously been shown to be associated with asthma, on TH1/TH2 lineage cytokines at birth.Methods and FindingsCord blood mononuclear cells (CBMCs) of 200 neonates were genotyped for two TBX21 and three HLX1 SNPs. CBMCs were stimulated with innate (Lipid A, LpA; Peptidoglycan, Ppg), adaptive stimuli (house dust mite Dermatophagoides pteronyssinus 1, Derp1) or mitogen (phytohemagglutinin, PHA). Cytokines, T-cells and mRNA expression of TH1/TH2-related genes were assessed. Atopic diseases during the first 3 years of life were assessed by questionnaire answered by the parents.Carriers of TBX21 promoter SNP rs17250932 and HLX1 promoter SNP rs2738751 showed reduced or trendwise reduced (p≤0.07) IL-5, IL-13 and TNF-α secretion after LpA-stimulation. Carriers of HLX1 SNP rs2738751 had lower IL-13 levels following Ppg-stimulation (p = 0.08). Carriers of HLX1 exon 1 SNP rs12141189 showed increased IL-5 (LpA, p = 0.007; Ppg, p = 0.10), trendwise increased IL-13 (LpA), higher GM-CSF (LpA/Ppg, p≤0.05) and trendwise decreased IFN-γ secretion (Derp1+LpA-stimulation, p = 0.1). Homozygous carriers of HLX1 promoter SNP rs3806325 showed increased IL-13 and IL-6 (unstimulated, p≤0.03). In carriers of TBX21 intron 3 SNP rs11079788 no differences in cytokine secretion were observed. mRNA expression of TH1/TH2-related genes partly correlated with cytokines at protein level. TBX21 SNP rs11079788 carriers developed less symptoms of atopic dermatitis at 3 years of age (p = 0.03).ConclusionsPolymorphisms in TBX21 and HLX1 influenced primarily IL-5 and IL-13 secretion after LpA-stimulation in cord blood suggesting that genetic variations in the transcription factors essential for the TH1-pathway may contribute to modified TH2-immune responses already early in life. Further follow-up of the cohort is required to study the polymorphisms' relevance for immune-mediated diseases such as childhood asthma.

STAT6 polymorphisms are associated with neonatal regulatory T cells and cytokines and atopic diseases at 3 years

“…The changes in Th1, Th2, and pro‐inflammatory cytokine responses at protein level in our study depending on the STAT6 polymorphisms are in accordance with previous reports showing that genetic variants in important asthma/allergy‐related genes can modulate cytokine secretion already at birth . While STAT6 regulation can affect further downstream signaling, it may directly or indirectly regulate cytokine production.…”

“…While modulation of the immune system early in life is crucial for the development of childhood atopic diseases , it remains unknown whether STAT6 genetic variants are able to shape immune responses already at birth. Thus, we investigated the role of two relevant IgE‐associated STAT6 SNPs on cord blood immune responses, including Treg and T helper cell gene expression and cytokine responses.…”

Methylomic markers of persistent childhood asthma: a longitudinal study of asthma-discordant monozygotic twins

“…3 ). Of note, genetic variation in this gene has been previously associated with the development of childhood asthma [ 29 , 30 ] and cytokine secretion at birth [ 31 ]. We next tested the specificity of our persistent-asthma-associated DMPs, by comparing average within-twin DNA methylation differences at these loci in (i) an asthma-remission group, comprising of MZ twin pairs discordant for asthma at age 10 but concordant for no asthma phenotype at 18 ( n = 20 twin pairs), and (ii) concordant unaffected MZ twin pairs where neither twin had asthma at both ages 10 and 18 ( n = 19 twin pairs).…”

Differential Expression of Serum MicroRNAs Supports CD4+ T Cell Differentiation into Th2/Th17 Cells in Severe Equine Asthma

“…The third gene, HLX , is a Th1 specific transcription factor (TF) that interacts with another Th1 specific TF, T-box 21 ( TBX21 ) required for the Th1 cells maturation and Th1-specific cytokine expression, including high expression of IFNG and repression of IL4 expression [ 113 , 114 , 115 ]. Variation in the genes of both the TFs have been associated with childhood asthma and variation within HLX significantly decreased its activity [ 116 , 117 , 118 ].…”