1. ¹Rheumatology Section, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London, UK
2. ²Department of Immunology, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London, UK

Correspondence: Dr BJ Morley, Rheumatology Section, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. E-mail: b.morley@ic.ac.uk

³Current Address: Gilead Sciences Inc. 333 Lakeside Drive, Foster City, CA 94404, USA.

Received 29 November 2004; Revised 10 February 2005; Accepted 10 February 2005; Published online 7 April 2005.

Abstract

The activation-induced differentiation of naive CD4⁺ T cells generates functionally divergent type 1 helper T cells (Th1) or type 2 helper T cells (Th2) effector cell populations, characterized by secretion of Interferon (IFN)- or Interleukin (IL)-4, respectively. Inappropriate generation of Th subsets may contribute to immune dysfunction. The decision to generate Th1/Th2 lineages is critically regulated by cytokines, such that IL-12 induces Th1 differentiation, while IL-4 induces Th2 differentiation. Genetic factors influence the pathway of Th differentiation, as displayed by the preferential generation of divergent Th populations by different inbred strains of mice. We employ two complementary genetic techniques to identify genes that regulate the default IL-4 secretion profiles of T cells from BALB/c and B6 mice. We performed a genome-wide linkage analysis of the progeny of a backcross between BALB/c and B6 mice to identify three loci, T-cell secretion of interleukin-4 (Tsi)1–3, on chromosomes 7, 19 and 15, respectively, which regulate in vitro T-cell IL-4 production. We have also employed mRNA representational difference analysis to isolate a gene, Flj20274, which is differentially expressed in T cells that secrete high levels of IL-4. Significantly, Flj20274 was mapped to the point of peak linkage within Tsi1 and is a strong candidate for Tsi1.