Trends in Immunology
Update
Research FocusThe complex issue of regulating perforin expression
Research Focus
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Perforin is an essential lymphocyte effector molecule
In both humans and mice, the absence of functional perforin can cause a severe immune deficiency state and/or disordered lymphoid and myeloid homeostasis 1, 2. For example, gene-engineered mice with two disrupted PRF1 alleles are killed by 10 000- to 100 000-times fewer infectious ectromelia (mouse poxvirus, corresponding to human smallpox or bovine cowpox) particles than wild-type mice [3]. Perforin-deficient mice are also highly prone to fatal, disseminated B cell lymphoma that develops in >60%
Regulation of perforin gene expression
In contrast to previous, failed attempts to identify regions of the perforin locus that recapitulate PRF1 regulation faithfully, Pipkin et al.[12] used microcell-mediated chromosome transfer to harvest an intact human chromosome 10 from fibroblasts (in which PRF1 is silent) and insert it into the mouse cytotoxic T lymphocyte (CTL) line SAM19. In seven of seven CTL clones tested, the human perforin gene was expressed at similar levels to the endogenous Prf1 (mouse) gene, and perforin expression
Concluding remarks and future perspectives
The major steps made by Pipkin et al.[12] and outlined here provide an impetus for further studies on PRF1 regulation. Having defined the regions of DNA, which presumably must bind to the specific transcription factors (TFs) driving perforin expression, the search will be on in earnest to identify which TFs bind at the active chromatin domain or LCR of PRF1, and in what physiological context, be it in response to cues received during development or T cell activation. As noted by Pipkin et al.,
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