The transcriptional control of the perforin locus.
Natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) use cytotoxic granules containing perforin and granzymes to lyse infected or malignant host cells, thereby providing immunity to intracellular microbes and tumors. Perforin is essential for cytotoxic granule-mediated killing. Perforin expression is regulated transcriptionally and correlates tightly with the development of cells that can exhibit cytotoxic activity. Although a number of genes transcribed by T cells and NK cells have been studied, the cell-specificity of perforin gene expression makes it an ideal model system in which to clarify the transcriptional mechanisms that guide the development and activation of cytotoxic lymphocytes. In this review, we discuss what is known about perforin expression and its regulation, then elaborate on recent studies that utilized chromosome transfer and bacterial artificial chromosome transgenics to define a comprehensive set of cis-regulatory regions that control transcription of the human PRF1 gene in a near-physiologic context. In addition, we compare the human and murine Prf1 loci and discuss how transcription factors known to be important for driving CTL differentiation might also directly regulate the cis-acting domains that control Prf1. Our review emphasizes how studies of PRF1/Prf1 gene transcription can illuminate not only the mechanisms of cytotoxic lymphocyte differentiation but also some basic principles of transcriptional regulation.
Department of Signaling and Gene Expression, The La Jolla Institute of Allergy and Immunology, La Jolla, CA 92037, USA. mpipkin@liai.org
Matthew E
ME
Pipkin
Anjana
A
Rao
Mathias G
MG
Lichtenheld
D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D054353:Perforin / Q000235:genetics* / Q000378:metabolism; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; D014157:Transcription Factors; C510467:perforin 1, mouse; D054353:Perforin