Characterization of the role of NLRC5 in immune responses and malignant transformation

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Immunity towards viral pathogens pivotally depends on induction of cell-autonomous type I interferon responses and on presentation of viral antigen by major histocompatibility class I (MHC class I) mole-cules to cells of the adaptive immune system. Importantly, cytotoxic T cell responses mediated by MHC class I restricted antigen presentation also play an important role in the elimination of malignant transformed cells. We recently showed that the human NLRC5 protein is involved in mounting type I interferon respons-es, as well as in the regulation of MHC class I gene expression. These two functions likely depend on the differential sub-cellular localization of NLRC5 in the cytosol and the nucleus. Of note, such a dual specificity for an innate immune regulatory protein is quite unique, making NLRC5 a very interesting protein to study.NLRC5 is a member of the "nucleotide-binding domain, leucine rich repeat containing protein" (NLR) family. Many members of this family are ell known to play import roles in innate and adaptive immune responses in humans. Of note, for the NLR-member, MHC class II transcriptional activator (CIITA), it is well established that this NLR acts as the master regulator of MHC class II gene expression. It was speculated that a similar factor that drives MHC class I gene expression might exist. Our recent results suggest that NLRC5 is this long sought-after protein that drives MHC class I gene expression. Although, the exact function of NLRC5 both in the regulation of type I interferon responses and MHC class I gene regulation still remains largely elusive at present. The laboratory of the applicant has a long standing research interesting in the molecular characteriza-tion of the function of human NLR proteins. Here, we request funding of a project aiming to decipher the detailed molecular mechanisms underlying the role of NLRC5 in anti-viral cell-autonomous re-sponses and in the regulation of MHC class I gene expression. Furthermore, we will address the role of NLRC5 in CD8 T cell mediated killing of virus-infected and transformed cells.Anticipated results of this project will provide important novel insights into fundamental processes of immunity, in particular the regulation of the expression of MHC class I genes.