Functional significance of the Fas molecule in naive lymphocytes

The Fas molecule mediates apoptotic signal in many cell types. Mouse mutations (Ipr, Ipr(cg), gld), which impair the function of Fas, cause spontaneous autoimmune disease. We generated Fas-deficient (Fas(-/-)) mice by homologous recombination. In embryonic stem cells Fas(-/-) mice developed Ipr-like disease, confirming that the abnormality of Fas is causal in the Ipr phenotype. We also made Fas(-/-) chimeric mice composed of a mixture of Fas(+/+) and Fas(-/-) cells. The chimeric mice also showed the Ipr phenotype. In Fas(-/-) chimeric mice, the Fas-deficient population expanded progressively among mature T and a lymphocytes. The expansion of Fas-deficient lymphocytes occurred at the naive, pre-primed, lymphocyte stage. These results suggest that the Fas molecule functions not only after antigenic stimulation, as previously hypothesized, but also at the naive lymphocyte stage.