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NLRC5 deficiency selectively impairs MHC class I- dependent lymphocyte killing by cytotoxic T cells

Staehli, Francesco
Ludigs, Kristina
Heinz, Leonhard X
Ferrero, Isabel
Braun, Marion
Schroder, Kate
Rebsamen, Manuele
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Published in The Journal of immunology. 2012, vol. 188, no. 8, p. 3820-8
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.
Keywords Adaptive ImmunityAnimalsAntigen-Presenting Cells/cytology/immunologyBone Marrow/immunologyCell DifferentiationCell Line, TumorCell Nucleus/genetics/immunologyCell ProliferationGene Expression RegulationGenes, MHC Class IHumansImmunity, InnateIntracellular Signaling Peptides and Proteins/genetics/immunologyKiller Cells, Natural/cytology/immunologyMacrophages/cytology/immunologyMiceMice, KnockoutNF-kappa B/genetics/immunologyT-Lymphocytes, Cytotoxic/cytology/immunology
PMID: 22412192
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Research group Groupe Reith Walter (pathologie et immunologie) (282)
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STAEHLI, Francesco et al. NLRC5 deficiency selectively impairs MHC class I- dependent lymphocyte killing by cytotoxic T cells. In: The Journal of immunology, 2012, vol. 188, n° 8, p. 3820-8. doi: 10.4049/jimmunol.1102671 https://archive-ouverte.unige.ch/unige:29176

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Deposited on : 2013-08-12

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