Tipping the balance of immune response

When the immune system encounters a potential threat, antigen-presenting cells deliver chunks of protein from the invading pathogen to naive helper T cells.

These naive cells respond by differentiating into one of two classes of mature helper T cells: TH1 cells, which mobilize the immune system against viruses and other intracellular pathogens, and TH2 cells, which drive the response against blood-borne threats, such as the parasitic disease leishmaniasis.

Interleukin-4 (IL-4), one of a class of signalling factors known as cytokines, drives TH2 differentiation and triggers secretion of additional IL-4, resulting in a positive feedback loop that fuels TH2 production while suppressing TH1 production. The degree of initial IL-4 production varies considerably between individuals and the resulting ‘TH2 bias’ can have serious clinical implications. “TH2 bias is thought to be a mirror of allergic response, because many TH2 cytokines tightly associate with pathology of allergy,” says Masato Kubo, of the RIKEN Research Center for Allergy and Immunology in Yokohama.

TH2 bias also varies between different mouse strains, a fact that Kubo, Mark Bix of St. Jude’s Children’s Research Hospital in Memphis, USA, and colleagues exploited in a recent effort to identify determinants for this trait1. It was known that BALB/c strain mice have a high TH2 bias—producing large quantities of IL-4 following T cell activation—while B10.D2 mice have a 50-fold lower bias. However, a hybrid BALB/c strain generated by Kubo and Bix that contains a chunk of chromosome 16 from the B10.D2 strain also exhibited low bias, suggesting that this segment includes a gene pertinent to this characteristic.

Closer analysis spotlighted the Mina gene as a likely suspect; analysis of various mouse strains revealed that Mina gene activity and levels of Mina protein were inversely correlated with TH2 bias. Bix and Kubo’s team subsequently determined that Mina assembles into a larger multi-protein complex that directly binds to and inhibits the gene encoding IL-4, supporting a key role for this factor in TH2 bias.

The team’s analysis also identified nearly two dozen sequence variations in Mina that correlate with gene activity levels. These so-called single-nucleotide polymorphisms (SNPs) could provide useful diagnostic tools, and Kubo and Bix are now exploring this potential. “We have already done large-scale SNP analysis with Japanese and US populations,” says Kubo. “The human Mina locus has several SNPs, and some of them have weak correlation with atopic asthma in the Japanese population, but not in the US [population].”

The corresponding author for this highlight is based at the Laboratory for Signal Network, RIKEN Research Center for Allergy and Immunology

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1. Okamoto, M., van Stry, M., Chung, L., Koyanagi, M., Sun, X., Suzuki, Y., Ohara, O., Kitamura, H., Hijikata, A., Kubo, M. & Bix, M. Mina, an IL4 repressor, controls T helper type 2 bias. Nature Immunology 10, 872–879 (2009).