Rfx7: important transcription factor for natural killer cell-mediated immunity
on Tuesday, July 3, 2018
A collaborative project between Swiss teams from the University and the Ludwig Center for Cancer Research of Lausanne, the ETH and the University of Zurich, and a team of researchers from the Centre d’Immunologie de Marseille-Luminy, led by Greta Guarda, from the Institute of Research in Biomedicine (IRB), Bellinzona, affiliated to the Università della Svizzera italiana, discovered that a novel protein called Rfx7 is important for natural killer (NK) cell-mediated immunity. The results of this study were published yesterday on Nature Immunology. The work was supported by the European Research Council and the Swiss National Science Foundation.
Regulatory factor X (Rfx) transcription factors, which regulate - turn on and off - genes in order to make sure that they are expressed in the right cell at the right time and in the right amount, are involved in development and organ function, as well as in immunity. The family member Rfx7, which is highly expressed in immune cells, remained functionally uncharacterized in mammalian cells. However, emerging evidence highlights an implication of this gene in the development of tumors, in particular of lymphoid origin, such as leukemia and lymphomas. Thus, these teams decided to study the role of this factor.
Rfx7-deficient NK cells exhibit deregulated expression of metabolism-related genes. Here are reported some of the top-ranked differentially expressed genes consistently altered in the bone marrow and spleen.
When Rfx7 is fully absent, the organisms presented a complex phenotype, exhibiting developmental defects. Therefore, the teams focused on the study of Rfx7 exclusively in the hematopoietic compartment. They found that Rfx7 was essential for NK cell maintenance, as in its absence the numbers of NK cells were significantly reduced. As a consequence, Rfx7 was also necessary for NK cell–mediated immunity as, for instance, the early control of cytomegalovirus infection was compromised. Transcriptomic approaches indicated that Rfx7 regulates a network of genes involved in controlling cellular metabolism. Indeed, further analyses showed that Rfx7 acts as a gatekeeper of NK cell quiescence, a prerequisite for their maintenance under resting conditions.
Altogether, these data indicate that it is not solely important to be correctly activated, but also to be properly resting, a concept often neglected in immunity. Moreover, the observation that Rfx7 acts as a transcriptional brake to lymphocyte activation is likely to be relevant in the context of tumor development, a research direction pursued now in the laboratory of Greta Guarda.
The group of Greta Guarda initiated its activities at the IRB in March 2018. Greta Guarda studied Molecular Biology at the University of Zurich and at the Swiss Federal Institute of Technology, Zurich. Then, she carried out her PhD work at the IRB and her post-doctoral studies at the University of Lausanne. She was appointed senior lecturer at the University of Lausanne in 2010 and assistant professor in 2012.
The transcription factor Rfx7 limits metabolism of NK cells and promotes their maintenance and immunity.
Wilson Castro, Sonia T. Chelbi, Charlène Niogret, Cristina Ramon-Barros, Suzanne P. M. Welten, Kevin Osterheld, Haiping Wang, Giorgia Rota, Leonor Morgado, Eric Vivier, Miro E. Raeber, Onur Boyman, Mauro Delorenzi, David Barras, Ping-Chih Ho, Annette Oxenius and Greta Guarda.
Nature Immunology, DOI: 10.1038/s41590-018-0144-9