Regulation of Class I Major Histocompatibility Complex (MHC) by Nucleotide-binding Domain, Leucine-rich Repeat-containing (NLR) Proteins

Most of the nucleotide-binding domain, leucine-rich repeat (NLR) proteins regulate responses to microbial and damage-associated products. Class II transactivator (CIITA) has a distinct function as the master regulator of class II major histocompatibility complex (MHC-II) transcription. Recently, human NLRC5 was found to regulate MHC-I in cell lines; however, a host of conflicting positive and negative functions has been attributed to this protein. To address the function of NLRC5 in a physiologic setting, we generated an Nlrc5(-/-) strain that contains a deletion in the exon that encodes the nucleotide-binding domain. We have not detected a role for this protein in cytokine induction by pathogen-associated molecular patterns and viruses. However, Nlrc5(-/-) cells showed a dramatic decrease of classical (H-2K) and nonclassical (Tla) MHC-I expression by T/B lymphocytes, natural killer (NK) cells, and myeloid-monocytic lineages. As a comparison, CIITA did not affect mouse MHC-I expression. Nlrc5(-/-) splenocytes and bone marrow-derived macrophages were able to up-regulate MHC-I in response to IFN-gamma; however, the absolute levels of MHC-I expression were significantly lower than WT controls. Chromatin immunoprecipitation of IFN-gamma-treated cells indicates that Nlrc5 reduced the silencing H3K27me3 histone modification, but did not affect the activating AcH3 modification on a MHC-I promoter. In summary, we conclude that Nlrc5 is important in the regulation of MHC-I expression by reducing H3K27me3 on MHC-I promoter and joins CIITA as an NLR subfamily that controls MHC gene transcription.