Like armed guards, natural killer (NK) cells are ready to respond immediately to attack. The constitutive expression of perforin, which facilitates the delivery of apoptosis-inducing granzymes to target cells, is essential for this state of readiness. But, little is known about how perforin gene expression is regulated. Now, a study in Immunity shows that the transcription factor MEF, which is encoded by a gene located on human chromosome Xq26, is essential for the expression of perforin by NK cells, and it provides clues to the basis of a human genetic disease.
ETS-family members have been shown previously to regulate the expression of perforin, but the specific proteins involved have not been identified. ETS1 and MEF are possible candidates.
In this study, Lacorazza and co-workers generated Mef-deficient mice. Similar to Ets1-deficient mice, T- and B-cell development were normal, but the number of NK cells was reduced markedly in the Mef-deficient mice. Bone-marrow-transfer experiments showed that this was owing to a developmental defect, rather than to an abnormal microenvironment. So, MEF and ETS1 might work together to promote development of the NK-cell lineage.
In addition, Mef−/− NK cells could not kill tumour-cell targets and contained little or no perforin, even after activation. However, perforin expression was induced normally in CD8+ T cells, which indicates that perforin expression is controlled by different mechanisms in NK cells and CD8+ T cells. Experiments with a reporter gene construct confirmed that the perforin promoter is activated strongly by Mef, but not by Ets1.
As Mef-deficient mice age, they develop perivascular lymphocytic infiltration, which is similar to the symptoms of familial haemophagocytic lymphohistiocytosis (FHL). Patients with FHL have defective NK cells, and some have mutations in the perforin gene. This study indicates that it could be worth looking for MEF mutations in male patients with FHL.
ORIGINAL RESEARCH PAPER
Lacorazza, H. D. et al. The ETS protein MEF plays a critical role in perforin gene expression and the development of natural killer and NK-T cells. Immunity 17, 437–449 (2002)