Developing alphabeta T cells diverge into the CD4 and CD8 lineages as they mature in the thymus. It is unclear whether lineage commitment is mechanistically distinct from the process that selects for the survival of T cells with useful T cell receptor (TCR) specificities (positive selection). In HD mice, which lack mature CD4+ T cells, major histocompatibility complex (MHC) class II-restricted T cells are redirected to the CD8 lineage independent of MHC class I expression. However, neither TCR-mediated signaling nor positive selection is impaired. Thus, the HD mutation provides genetic evidence that lineage commitment may be mechanistically distinct from positive selection.

We have identified a spontaneous mutation in mice, which we term HD for ''helper T cell deficient. ' . This is the first genetic defect of its kind to be described in the mouse and may prove highly informative in understanding the molecular pathways underlying lineage commitment.Developing ␣␤ T cells mature through three major stages characterized by differential expression of the coreceptor molecules CD4 and CD8. Initially, thymocytes express neither coreceptor (CD4 Ϫ CD8 Ϫ

: Human primary cells (e.g. adult stem cells) as well as differentiated cells, including those of the immune system, have been found to be therapeutically useful and free of ethical concerns. Several products have received market authorization and numerous promising clinical trials are underway. We believe that such primary therapeutic cells will dominate the market for cell therapy applications for the foreseeable future. Consequently, production of such cellular products warrants attention and needs to be a fully controlled pharmaceutical process. Thus, where possible, such production should change from manufacture towards a truly scalable industrialized process for both allogeneic and autologous products. Here, we discuss manufacturing aspects of both autogeneic and allogeneic products, review the field, and provide historical context.

The applicability of immunotherapy would be dramatically broadened to a greater number of recipients if direct ''offthe-shelf'' products could be engineered to engender functionally potent immune responses against true ''self''-tumor antigens. This would obviate the need for ex vivo culture of dendritic cells or T cells on a patient-bypatient basis, for example. The carcinoembryonic antigen (CEA) is a glycoprotein expressed in normal gut epithelium that is up-regulated in the majority of colon cancers, nonsmall cell lung cancers, and half of all breast cancers. Such properties make CEA an excellent and important target for cancer immunotherapy. In this study, we show stabilization of 14-day established s.c. mGC4CEA tumors in human CEA (huCEA) transgenic mice following two direct low-dose injections of 0.15 Â 10 6 transducing units of a lentiviral vector (LV) that directs expression of huCEA (LV-huCEA). This stabilization result was reproducible and detailed analyses including antibody assays, multiplex cytokine analyses on unstimulated splenocytes, lymph node cell characterizations, tetramer staining, and immunofluorescence staining of tumor sections showed that this outcome correlated with both a cellular and humoral immune response. Similar tumor outcomes were not seen when mice were vaccinated with a control LV that engineered expression of enGFP only. The long-term potency of this vaccination strategy was also studied and revealed the requirement for maintenance of tumor antigen-specific immunity for efficient tumor control. These data support the use of direct injections of low doses of LV-huCEA for enhancement of tumor immunotherapy directed against CEA. [Mol Cancer Ther 2009;8(3):692 -702]

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