title: NLRC5 deficiency selectively impairs MHC class I- dependent lymphocyte killing by cytotoxic T cells.
abstract: Nucleotide-binding oligomerization domain-like receptors (NLRs) are intracellular proteins involved in innate-driven inflammatory responses. The function of the family member NLR caspase recruitment domain containing protein 5 (NLRC5) remains a matter of debate, particularly with respect to NF-κB activation, type I IFN, and MHC I expression. To address the role of NLRC5, we generated Nlrc5-deficient mice (Nlrc5(Δ/Δ)). In this article we show that these animals exhibit slightly decreased CD8(+) T cell percentages, a phenotype compatible with deregulated MHC I expression. Of interest, NLRC5 ablation only mildly affected MHC I expression on APCs and, accordingly, Nlrc5(Δ/Δ) macrophages efficiently primed CD8(+) T cells. In contrast, NLRC5 deficiency dramatically impaired basal expression of MHC I in T, NKT, and NK lymphocytes. NLRC5 was sufficient to induce MHC I expression in a human lymphoid cell line, requiring both caspase recruitment and LRR domains. Moreover, endogenous NLRC5 localized to the nucleus and occupied the proximal promoter region of H-2 genes. Consistent with downregulated MHC I expression, the elimination of Nlrc5(Δ/Δ) lymphocytes by cytotoxic T cells was markedly reduced and, in addition, we observed low NLRC5 expression in several murine and human lymphoid-derived tumor cell lines. Hence, loss of NLRC5 expression represents an advantage for evading CD8(+) T cell-mediated elimination by downmodulation of MHC I levels-a mechanism that may be exploited by transformed cells. Our data show that NLRC5 acts as a key transcriptional regulator of MHC I in lymphocytes and support an essential role for NLRs in directing not only innate but also adaptive immune responses.
authors.affiliation: Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Staehli
authors.forename: Kristina
authors.initials: K
authors.lastname: Ludigs
authors.forename: Leonhard X
authors.initials: LX
authors.lastname: Heinz
authors.forename: Queralt
authors.initials: Q
authors.lastname: Seguín-Estévez
authors.forename: Isabel
authors.initials: I
authors.lastname: Ferrero
authors.forename: Marion
authors.initials: M
authors.lastname: Braun
authors.forename: Kate
authors.initials: K
authors.lastname: Schroder
authors.forename: Manuele
authors.initials: M
authors.lastname: Rebsamen
authors.forename: Aubry
authors.initials: A
authors.lastname: Tardivel
authors.forename: Chantal
authors.initials: C
authors.lastname: Mattmann
authors.forename: H Robson
authors.initials: HR
authors.lastname: MacDonald
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Walter
authors.initials: W
authors.lastname: Reith
authors.forename: Greta
authors.initials: G
authors.lastname: Guarda
authors.forename: Jürg
authors.initials: J
authors.lastname: Tschopp
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D005805:Genes, MHC Class I; D006801:Humans; D007113:Immunity, Innate; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C549161:NLRC5 protein, mouse