Fas (Apo-1/CD95) is a cell-surface receptor involved in cell death signaling. The key role of the Fas system in negative growth regulation has been studied mostly within the immune system, and somatic mutations of Fas gene in cancer patients have been described solely in lymphoid-lineage malignancies. However, many nonlymphoid tumor cells have been found to be resistant to Fas-mediated apoptosis, which suggests that Fas mutations, one of the possible mechanisms for Fas-resistance, may be involved in the pathogenesis of non-lymphoid malignancies as well. In this study, we have analysed the entire coding region and all splice sites of the Fas gene for the detection of the gene mutations in 65 human nonsmall cell lung cancers by polymerase chain reaction, single strand conformation polymorphism and DNA sequencing. Overall, ®ve tumors (7.7%) were found to have the Fas mutations, which were all missense mutations. Four of the ®ve mutations identi®ed were located in the cytoplasmic region (death domain) known to be involved in the transduction of an apoptotic signal and one mutation was located in the transmembrane domain. This is the ®rst report on the Fas gene mutations in non-lymphoid malignancies, and the data presented here suggests that alterations of the Fas gene might lead to the loss of its apoptotic function and contribute to the pathogenesis of some human lung cancers.

TH17 cells are recognized as a unique subset of T helper cells that have critical roles in the pathogenesis of autoimmunity and tissue inflammation. Although RORγt is necessary for the generation of TH17 cells, the molecular mechanisms underlying the functional diversity of TH17 cells are not fully understood. Here we show that a member of interferon regulatory factor (IRF) family of transcription factors, IRF8, has a critical role in silencing TH17-cell differentiation. Mice with a conventional knockout, as well as a T cell-specific deletion, of the Irf8 gene exhibited more efficient TH17 cells. Indeed, studies of an experimental model of colitis showed that IRF8 deficiency resulted in more severe inflammation with an enhanced TH17 phenotype. IRF8 was induced steadily and inhibited TH17-cell differentiation during TH17 lineage commitment at least in part through its physical interaction with RORγt. These findings define IRF8 as a novel intrinsic transcriptional inhibitor of TH17-cell differentiation.

Caspase 10 (Mch4/FLICE2) is a caspase homologous to caspase 8. A recent report described that inherited CASP10 gene mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome (ALPS). In this study, to explore the possibility that mutation of this gene might be involved in the development of nonHodgkin lymphoma (NHL), we have analyzed the entire coding region and all splice sites of the CASP10 gene for the detection of somatic mutations in 117 human NHLs. Overall, 17 NHLs (14.5%) were found to have CASP10 mutations, which were identified in the coding regions of the prodomain (n ‫؍‬ 3), the p17 large protease subunit (n ‫؍‬ 11), and the p12 small protease subunit (n ‫؍‬ 3). We expressed the tumor-derived caspase 10 mutants in 293 cells and found that apoptosis was suppressed. These data suggest that the inactivating mutations of the CASP10 gene might lead to the loss of its apoptotic function and contribute to the pathogenesis of some human NHLs. (Blood. 2002;99:4094-4099)

Forkhead box P3 (FOXP3)-positive regulatory T cells (Treg) are a unique subset of T cells with immune regulatory properties. Treg cells can be induced from non-Treg CD4+ T cells (induced Treg, iTreg) by T cell receptor (TCR) triggering, IL-2 and TGF-β or retinoic acid. 1,25(OH)2 vitamin D3 (VD3) affects the functions of immune cells including T cells. 1,25(OH)2VD3 binds the nuclear vitamin D receptor (VDR) that binds target DNA sequences known as the vitamin D response element (VDRE). Although 1,25(OH)2VD3 can promote FOXP3 expression in CD4+ T cells with TCR triggering and IL-2, it is unknown whether this effect of 1,25(OH)2VD3 is mediated through direct binding of VDR to the FOXP3 gene without involving other molecules. Also, it is unclear whether FOXP3 expression in 1,25(OH)2VD3-induced Treg (VD-iTreg) cells is critical for the inhibitory function of these cells. Here we demonstrated the presence of VDREs in the intronic conserved non-coding sequence (CNS) region +1714 to +2554 of the human FOXP3 gene and the enhancement of the FOXP3 promoter activity by such VDREs in response to 1,25(OH)2VD3. In addition, VD-iTreg cells suppressed the proliferation of target CD4+ T cells and this activity was dependent on FOXP3 expression. These findings suggest that 1,25(OH)2VD3 can affect human immune responses by regulating FOXP3 expression in CD4+ T cells through direct VDR binding to the FOXP3 gene which is essential for inhibitory function of VD-iTreg cells.