It should be noted that the CD4+ Th1/Th2 system is the predominant model in which IFN-y regulation has been studied, even though CD8+ T cells, NK, and NKT cells are important cellular sources of IFN-y. Nevertheless, recent findings have suggested cell-subset-specific regulation of IFN-y in CD8+ T cells. Given that T-bet is a critical component of IFN-y regulation and Th1 differentiation, it was curious that CD8+ cells in the T-bet-/- mice had seemingly normal
IFN-y expression. Eomesodermin (Eomes), a paralog of T-bet, was identified as a determinant of IFN-y expression in CD8+ T cells (Nawijn et al. 2001). Eomes is also implicated in other CD8+ effector T cell functions including the development of the cytotoxic machinery although the mechanism(s) through which Eomes regulates IFN-y expression have yet to be determined. Nevertheless, this work has been extended to indicate that T-bet and Eomes may have a cooperative role in determining some NK cell and CD8+ T cell-specific functions by regulating CD122 expression, which is part of the IL-2/IL-15 receptor complex (Intelkofer et al. 2005). The hypothesis of cooperation between T-bet and Eomes received support from the work of Hatton et al. (Hatton et al. 2006), who demonstrate by using a transgenic bacterial artificial chromosome (BAC) model to delete a CNS site that the deletion of the -22 kb CNS resulted in a loss of IFN-y expression in both CD4+ and CD8+ T cells in response to both T cell receptor and cytokine (IL-12 + IL-18) signaling. These developments provide another potential link between cytokine regulation of cell lineage decisions and gene expression profiles. In addition, the technology for manipulating BACs by bacterial recombineering, creating BAC transgenic mice, and using Cre-lox models has become more standardized and available, thus making it feasible to evaluate the discrete contributions of distal elements for appropriate gene expression profiles using in vivo models. This is preferable to transfection systems that cannot replicate the complex intrachromasomal interactions that are likely critical to distal enhancer function. Thus, the use of these in vivo tools is proving to be a robust approach for evaluating the genomic requirements for gene expression.
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