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Background  TBX21 (T cell specific T-box transcription factor) and HLX1 (H.20-like homeobox 1) are crucial transcription factors of T H 1-cells, inducing their differentiation and suppressing T H 2 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 T H 1/T H 2 lineage cytokines at birth.    Methods and Findings  Cord 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 T H 1/T H 2-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 T H 1/T H 2-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).    Conclusions  Polymorphisms 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 T H 1-pathway may contribute to modified T H 2-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.

TBX21 and HLX1 Polymorphisms Influence Cytokine Secretion at Birth