Genetic Regulation of Commitment to Interleukin 4 Production by a CD4+ T Cell–intrinsic Mechanism

Abstract

The dysregulated expression of interleukin 4 (IL-4) can have deleterious effects on the outcome of infectious and allergic diseases. Despite this, the mechanisms by which naive T cells commit to IL-4 expression during differentiation into mature effector cells remain incompletely defined. As compared to cells from most strains of mice, activated CD4+ T cells from BALB mice show a bias towards IL-4 production and T helper 2 commitment in vitro and in vivo. Here, we show that this bias arises not from an increase in the amount of IL-4 produced per cell, but rather from an increase in the proportion of CD4+ T cells that commit to IL-4 expression. This strain-specific difference in commitment was independent of signals mediated via the IL-4 receptor and hence occurred upstream of potential autoregulatory effects of IL-4. Segregation analysis of the phenotype in an experimental backcross cohort implicated a polymorphic locus on chromosome 16. Consistent with a role in differentiation, expression of the phenotype was CD4+ T cell intrinsic and was evident as early as 16 h after the activation of naive T cells. Probabilistic gene activation is proposed as a T cell–intrinsic mechanism capable of modulating the proportion of naive T cells that commit to IL-4 production.

Linkage analysis of the genetic determinants of T-cell IL-4 secretion, and identification of Flj20274 as a putative candidate gene

“…15 This replication of linkage in different experimental crosses, in the context of interrelated traits, strongly suggests that Tsi1 plays a true role in T-cell phenotype regulation, and has not been artefactually identified. The most significant finding of this study is the identification of the gene encoding putative protein FLJ20274 from high IL-4-expressing T cells by RDA, and demonstration that Flj20274 maps to and enhances the peak linkage of Tsi1.…”

“…Examination of CD4 þ cells from BALB/c and B6 mice revealed clearly divergent IL-4 secretion patterns (Figure 1a Figure 1a), suggesting a partially dominant inheritance of the IL-4 secretion phenotype, in keeping with previous observations. 15 Assays were performed over multiple separate occasions, with mice from different litters to ensure rigorous reproducibility of phenotype assignment during subsequent genetic analysis. Also, proliferation of cultured cells was confirmed by incorporation of tritiated thymidine, to ensure that low levels of IL-4 secretion were not due to failure of activation (data not shown).…”

“…Tsi1 may be related to previously described loci. 13,15 Tsi2 and Tsi3 represent novel chromosomal intervals. We have provided evidence that these three loci account for 70% of the phenotypic variance within our test mice, that no single locus is necessary and that each interval confers approximately equal individual additive effects to the overall T-cell IL-4 production capability of individual mice.…”

“…14 Similarly, mapping studies have attempted to dissect the in vitro regulation of Th2 differentiation, and have implicated a chromosome 7 locus in the regulation of T-cell IL-4 secretion. 15 However, in general, the application of linkage analysis alone only provides sufficient resolution to identify chromosomal regions that may span several cM and contain hundreds of candidate genes.…”

A SNP uncoupling Mina expression from the TGFβ signaling pathway

“…Originally discovered as a Myc‐induced nuclear antigen of 53 kDa with pro‐proliferative activity in promyelocytic leukemia HL60 cells 1, it has subsequently been shown to be overexpressed in a wide variety of human cancers, in some cases providing prognostic value 2. Independently, its encoding gene was mapped to a locus regulating Th2‐bias 3, 8, 9, a genetic trait defined as the propensity of naïve T helper cells to develop in vitro into IL4‐producing Th2 cells 9, 10 and it was shown to act as a dose‐dependent transcriptional corepressor of the gene encoding interleukin‐4 (IL4) 3, a key regulator of Th2 development 9, 10, 11, 12. Later work with Mina KO mice, however, revealed the dispensability of Mina for normal Th2 development, perhaps due to functional redundancy with its close evolutionary and structural paralog No66 13.…”