Axotrophin (axot) is a newly characterised stem cell gene and mice that lack axotrophin are viable and fertile, but show premature neural degeneration and defective development of the corpus callosum. By comparing axot+/+, axot+/- and axot-/- littermates, we now show that axotrophin is also involved in immune regulation. Both T cell proliferation and T cell-derived leukaemia inhibitory factor (LIF) were suppressed by axotrophin in a gene-dose-dependent manner. Moreover, a role for axotrophin in the feedback regulation of LIF is implicated. This is the first evidence that fate determination mediated by LIF maybe qualified by axotrophin.