NLRC5 shields T lymphocytes from NK-cell-mediated elimination under inflammatory conditions.

Kristina Ludigs,Greta Guarda,Daniel T Utzschneider,Anh Thu Dang,Giorgia Rota,Francesco Staehli,Stéphanie Bessoles,Dietmar Zehn,Werner Held,Wilson Castro,Camilla Jandus,Pedro Romero,Eric Vivier

doi:10.1038/ncomms10554

Abstract

NLRC5 is a transcriptional regulator of MHC class I (MHCI), which maintains high MHCI expression particularly in T cells. Recent evidence highlights an important NK–T-cell crosstalk, raising the question on whether NLRC5 specifically modulates this interaction. Here we show that NK cells from Nlrc5-deficient mice exhibit moderate alterations in inhibitory receptor expression and responsiveness. Interestingly, NLRC5 expression in T cells is required to protect them from NK-cell-mediated elimination upon inflammation. Using T-cell-specific Nlrc5-deficient mice, we show that NK cells surprisingly break tolerance even towards ‘self' Nlrc5-deficient T cells under inflammatory conditions. Furthermore, during chronic LCMV infection, the total CD8+ T-cell population is severely decreased in these mice, a phenotype reverted by NK-cell depletion. These findings strongly suggest that endogenous T cells with low MHCI expression become NK-cell targets, having thus important implications for T-cell responses in naturally or therapeutically induced inflammatory conditions.

Highlights

NLRC5 is a transcriptional regulator of MHC class I (MHCI), which maintains high MHCI expression in T cells
We analysed by quantitative real-time PCR H2-K and H2-D alongside with Nlrc[5] messenger RNA abundance in different tissues derived from control or Nlrc5-deficient mice
As we were interested in the role of NLRC5 in T cells, we further analysed the non-classical MHCI Qa2, recently shown by us to be a prime target of NLRC5, and H2-M3

Summary

Introduction

NLRC5 is a transcriptional regulator of MHC class I (MHCI), which maintains high MHCI expression in T cells. During chronic LCMV infection, the total CD8 þ T-cell population is severely decreased in these mice, a phenotype reverted by NK-cell depletion These findings strongly suggest that endogenous T cells with low MHCI expression become NK-cell targets, having important implications for T-cell responses in naturally or therapeutically induced inflammatory conditions. As recently shown by chromatin immunoprecipitation sequencing, NLRC5 is exclusively dedicated to regulate the classical MHCI genes H2-K and H2-D, and beta-2 microglobulin (B2m) and selected non-classical MHCI genes by occupying a specific SXY sequence in their promoter[2] This NLR is constitutively expressed at high levels in immune cells and predominantly in lymphocytes[1]. The authors detected a very low expression of classical and non-classical MHCI on Ifnar À / À T cells as compared with their wild-type counterparts, suggesting a straightforward explanation for eliciting NK-cell rejection[15]

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