Five unrelated children are described with a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive nonmalignant lymphadenopathy, autoimmune phenomena, and expanded populations of TCR-CD3+CD4-CD8- lymphocytes. These findings, suggesting a genetic defect in the ability of T lymphocytes to respond to normal immunoregulatory mechanisms, prompted an evaluation of lymphocyte apoptosis. Each child had defective Fas-mediated T lymphocyte apoptosis associated with a unique, deleterious Fas gene mutation. One mutation appeared to cause a simple loss of function; however, four others had a dominant negative phenotype when coexpressed with normal Fas. Family studies demonstrated the inheritance of the mutant Fas alleles. The occurrence of Fas mutations together with abnormal T cell apoptosis in ALPS patients suggests an involvement of Fas in this recently recognized disorder of lymphocyte homeostasis and peripheral self-tolerance.

T-cell receptor-induced apoptosis regulates immune responses and can result from interactions between Fas (Apo1/CD95) and Fas ligand (FasL). Mutations in the genes for Fas and FasL cause disorders resembling human autoimmune diseases in lpr and gld mice, respectively. However, peripheral T-cell deletion takes place in lpr mice, and autoimmune syndromes occur in mouse strains without Fas or FasL defects. Here we show that tumour necrosis factor (TNF) can mediate mature T-cell receptor-induced apoptosis through the p75 TNF receptor. Blockage of both TNF and FasL is required to abrogate T-cell death and TNF mediates the death of most CD8+ T cells, whereas FasL mediates the death of most CD4+ T cells. Our results suggest that autoregulatory apoptosis of the mature T cells can occur by two distinct molecular mechanisms.

To investigate the role of an activated K-Ras gene in the initiation and maintenance of lung adenocarcinomas, we developed transgenic mice that express murine K-Ras4b G12D under the control of doxycycline in type II pneumocytes. Focal proliferative lesions of alveolar type II pneumocytes were observed as early as seven days after induction with doxycycline; after two months of induction, the lungs contained adenomas and adenocarcinomas, with focal invasion of the pleura at later stages. Removal of doxycycline caused a rapid fall in levels of mutant K-Ras RNA and concomitant apoptotic regression of both the early proliferative lesions and the tumors. Tumor burden was dramatically decreased by three days after withdrawal, and tumors were undetectable after one month. When similar experiments were performed with animals deficient in either the p53 gene or the Ink4A/Arf locus, tumors arose more quickly (within one month of exposure to doxycycline) and displayed more obvious histological features of malignancy; nevertheless, these tumors also regressed rapidly when the inducer was removed, implying that continued production of mutant K-Ras is necessary to maintain the viability of tumor cells in the absence as well as the presence of tumor suppressor genes. We also show that the appearance and regression of these pulmonary tumors can be readily monitored in anesthetized transgenic animals by magnetic resonance imaging. The vast majority (80%-90%) of cases are related to tobacco smoking; ∼10% of smokers will develop lung cancer with a peak incidence in the fifth and sixth decades of life (Shopland et al. 1991). Adenocarcinoma, a form of non-small cell lung cancer (NSCLC), is the most common type, now accounting for >40% of all lung cancer cases (Ginsberg et al. 2001). Analysis of resected tumors has revealed several frequent molecular changes (Salgia and Skarin 1998;Gazdar and Minna 1999;Forgacs et al. 2001). K-Ras is mutated to an activated form in ∼30% of NSCLCs, c-Myc is up-regulated in 20%-30%, the p53 tumor suppressor gene is mutated or deleted in ∼50%, and the Ink4A/Arf locus is often deleted or hypermethylated. K-Ras mutations are also observed in a substantial number of sporadic and chemically induced lung adenocarcinomas in mice (Manam et al. 1992;Cazorla et al. 1998;Tuveson and Jacks 1999).The probable precursors to lung adenocarcinomas are either type II alveolar epithelial cells or Clara cells (Malkinson 1991;Rehm et al. 1991). Transgenic mouse models of lung cancer have been produced by expressing potent viral oncogenes in these cell types (Glasser et al. 1994). Although such models confirm that type II pneumocytes and Clara cells are likely precursors to lung adenocarcinomas, they have not been built with the genes known to be altered in human lung cancer. Another limitation, as in all traditional transgenic models, is that the transgene may be expressed during development and thus may not mimic somatically acquired mutations ac- Cold Spring Harbor Laboratory Press on May 9, 2018 -Published by genesdev.c...