PT Unknown AU Ehmke, M TI NLRC5: An NLR member with impact on adaptive and innate immune mechanisms and its protective role in the progression of colitis PY 2016 PU Christian-Albrechts-Universität zu Kiel WP https://macau.uni-kiel.de/receive/diss_mods_00018068 LA en DE NOD-like receptor; MHC I; inflammatory bowel disease; IBD; NLRC5; NLR; Chronisch entzündliche Darmerkrankungen AB NLRC5 was reported to influence the expression of IFNs and NF κB target genes as well as the production of IL 1β. However, its impact is still controversial. NLRC5 was identified to share several features with CIITA, an NLR member that functions as co-transcriptional activator for MHC class II-encoding genes and is therefore essential for adaptive immunity. In analogy, NLRC5 was reported to initiate the transcription of MHC class I-encoding genes. This study aimed to define the contribution of NLRC5 to innate as well as adaptive immune mechanisms. Nlrc5-deficient (ko) mice were generated. They were viable and fertile and had no obvious immune defects under SPF-housing conditions. NLRC5 was predominantly expressed in immune tissues and potently induced by IFNɣ. In accordance with its role as transcriptional regulator, Nlrc5 ko mice had a severely decreased MHC class I surface expression. However, a residual, cell type-dependent MHC class I expression remained. Furthermore, MHC class I was still inducible in Nlrc5-deficient cells, which pointed to the existence of other MHC I regulating mechanisms. It is assumed that one of these mechanisms is the transcriptional activation of MHC class I-coding genes by CIITA. Decreased MHC class I levels led to an impaired generation of CD8+ T lymphocytes in Nlrc5 ko mice. The MHC class II+ cell population was increased, but did not affect the number of CD4+ T lymphocytes. Next to adaptive immune functions, NLRC5 was involved in innate immune signaling pathways. The protein was crucial for a proper induction of type I and II IFNs as well as IL 1β. The diminished CD8+ T cell population and the impaired production of IFNγ and IL 1β were presumed to render Nlrc5 ko mice less susceptible to intestinal inflammation. In contrast this work revealed that ko mice develop an aggravated DSS-induced colitis. The pronounced phenotype correlated with an enhanced epithelial destruction and an upregulated production of inflammatory cytokines. PI Kiel ER