Regulatory factor X (RFX) 7 belongs to a family of conserved transcription factors. Whereas RFX family members are known to play a rôle in ciliogenesis and immunity, the function of RXF7 remains completely uncharacterized. RFX5 is the closest homologue to RFX7 in terms of protein structure and is crucial for the transcription of major histocompatibility complex (MHC) genes. Expression of MHC molecules has several functions: one is the présentation of invading pathogens to immune cells called T lymphocytes, which fight the infection; second, it allows to regulate the activity of Natural Killer (NK) cells to eliminate infected or cancerous cells. Given the similarity to RFX5, we hypothesized that RFX7 contributes to MHC transcription and immunity.
We observed prominent Rfx7 expression in immune organs and lymphoid cells. We thus generated mice with specific R/x7-deletion in the hematopoietic compartment. Assessment of MHC surface levels revealed low expression of selected non-classical MHC class I molecules in R/x7-deficient T cells. Further, we showed that Rfx7 localized to the nucleus where it controls the expression of these genes, as demonstrated also by complementary genomic approaches. These results uncover therefore the rôle of Rfx7 as a novel transcriptional regulator of MHC genes.
Interestingly, functional experiments showed that /?/x7-deficient mice had defective NK cell- mediated immunity. A closer analysis revealed a decrease in the numbers of mature NK lymphocytes, which was due to an NK cell intrinsic maintenance problem. Genomic approaches on fl/x7-deleted and control NK cells led to the identification of negative regulators of cell metabolism among the top Rfx7 target genes. Remarkably, R/x7-deficient NK cells presented spontaneous features of activation. In agreement, R/x7-deficient NK cells were rescued in the presence of activating cytokines in vitro and in vivo. These results indicated that NK cells were not inherently defective, but rather adapted to a heightened metabolic state. Interestingly, this altered metabolic state was not exclusive to NK cells, but common to most lymphocytes. This observation could be relevant to explain the association of RFX7 altérations to leukemia. Rfx7 emerges therefore as a gatekeeper of a resting state in lymphoid cells and - most remarkably - in NK cells, which is a prerequisite to warrant optimal innate cytotoxic responses.