Genetic regulation of commitment to interleukin 4 production by a CD4(+) Tcell-intrinsic mechanism

The dysregulated expression of interleukin 4 (IL-4) can have deleterious ef fects on the outcome of infectious and allergic diseases. Despite this, the mechanisms by which naive T cells commit to IL-4 expression during differe ntiation into mature effector cells remain incompletely defined. As compare d to cells from most strains of mice, activated CD4(+) cells from BALB mice show that a bias towards IL-4 production and T helper 2 commitment in vitr o 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 pr oportion of CD4(+) T cells that commit to IL-4 expression. This strain-spec ific difference in commitment was independent of signals mediated via the I L-4 receptor and hence occurred upstream of potential autoregulatory effect s of IL-4. Segregation analysis of the phenotype in an experimental backcro ss cohort implicated a polymorhpic locus on chromosome 16. Consistent with a role in differentiation, expression of the phenotype was CD4(+) T cell in trinsic and was evident as early as 16 h after the activation of naive T ce lls. Probabilistic gene activation is proposed as a T cell-intrinsic mechan ism capable of modulating the proportion of naive T cells that commit to IL -4 production.