Host resistance to a gastrointestinal parasite regulated by a SNP modulating SMAD3 binding to a TGFβ-regulated transcriptional enhancer of Mina, encoding an immunoregulatory member of the Jmjc protein family (70.9)

Abstract

Abstract In a hunt for Th2-bias regulatory loci in mice, we have used interval-specific congenic mapping to positionally clone a gene called Mina, encoding an immunoregulatory member of the JmjC protein family. Th2-bias is a genetic trait defined as the propensity of naïve T helper cells to develop in vitro under neutral conditions into T helper 2 (Th2) effector cells. Th2 cells play a critical role in host protection from multicellular parasites such as intestinal helminths and when disregulated contribute to allergic diseases such as asthma. The Th2-bias trait is known to vary across different inbred mouse strains and correlates inversely with the relative abundance of intracellular Mina protein. Adding further support for a causal link between Mina protein level and Th2-bias, Mina was shown to act as a dose-dependent transcriptional corepressor of the gene encoding interleukin-4 (IL4), a key regulator of Th2 development. We have now identified a SNP that explains differential Mina expression level in high and low Th2-biased strains such as BALB/c and C57BL/6. Most interestingly, this SNP acts by modulating SMAD3 binding to a TGFβ-regulated intronic Mina enhancer. We are currently tying this into its physiological role in pulmonary inflammation and intestinal helminth infection using Mina conditional KO mice, which exhibit dramatic phenotypes in both models.