Final Report Summary - TRANSCRIPTIONALNLRS (NLRs AS TRANSCRIPTIONAL REGULATORS)
Major histocompatibility complex (MHC) molecules are the core of vertebrate immunology, representing the link between the innate and adaptive immune system and being crucial for the education and activation processes of lymphocytes. As such, MHCs are involved in all types of immunological disorders, from immunodeficiency to autoimmunity. Results by us and others showed that NLR, CARD Domain Containing 5 (NLRC5) is an essential transcriptional regulator of MHC class I in immune cells.
Our recent work has contributed to the understanding of NLRC5’s physiological function, showing that it protects CD8+ T cells from NK cell-mediated rejection upon inflammation or viral infection. Further, through genomic and genetic approaches, we pinpointed the focused activity of NLRC5 in regulating the MHC class I pathway and advanced our understanding of the mechanisms underlying NLRC5 transcriptional regulatory function, e.g. demonstrating the importance of the DNA-binding protein Regulatory factor 5 (Rfx5) to NLRC5-driven gene transactivation. We thus gained further insights into the dovetailed system that governs MHC expression.
These findings roused our interest into Rfx7, an uncharacterized transcription factor with homology to Rfx5 and highly expressed in immune cells. We observed that Rfx7 is essential for NK cell maintenance, acting as a gatekeeper of metabolic quiescence. As a consequence, Rfx7 is also necessary for NK cell-mediated immunity in vivo. These data highlight how it is important to be properly resting and might explain the genetic association of RFX7 with lymphoid malignancies. Altogether, we identified here novel aspects linked to NLRC5 and Rfx7 relevant for the immune response and potentially also for a number of different pathological conditions.
Our recent work has contributed to the understanding of NLRC5’s physiological function, showing that it protects CD8+ T cells from NK cell-mediated rejection upon inflammation or viral infection. Further, through genomic and genetic approaches, we pinpointed the focused activity of NLRC5 in regulating the MHC class I pathway and advanced our understanding of the mechanisms underlying NLRC5 transcriptional regulatory function, e.g. demonstrating the importance of the DNA-binding protein Regulatory factor 5 (Rfx5) to NLRC5-driven gene transactivation. We thus gained further insights into the dovetailed system that governs MHC expression.
These findings roused our interest into Rfx7, an uncharacterized transcription factor with homology to Rfx5 and highly expressed in immune cells. We observed that Rfx7 is essential for NK cell maintenance, acting as a gatekeeper of metabolic quiescence. As a consequence, Rfx7 is also necessary for NK cell-mediated immunity in vivo. These data highlight how it is important to be properly resting and might explain the genetic association of RFX7 with lymphoid malignancies. Altogether, we identified here novel aspects linked to NLRC5 and Rfx7 relevant for the immune response and potentially also for a number of different pathological conditions.