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NK cells promote islet allograft tolerance via a perforin-dependent mechanism

A Corrigendum to this article was published on 01 March 2006

This article has been updated

Abstract

Although major histocompatibility complex (MHC) class II–restricted CD4 T cells are well appreciated for their contribution to peripheral tolerance to tissue allografts, little is known regarding MHC class I–dependent reactivity in this process. Here we show a crucial role for host MHC class I–dependent NK cell reactivity for allograft tolerance in mice induced through either costimulation blockade using CD154-specific antibody therapy or by targeting LFA-1 (also known as CD11a). Tolerance induction absolutely required host expression of MHC class I, but was independent of CD8 T cell–dependent immunity. Rather, tolerance required innate immunity involving NK1.1+ cells, but was independent of CD1d-restricted NKT cells. Therefore, NK cells seem to be generally required for induction of tolerance to islet allografts. Additional studies indicate that CD154-specific antibody–induced allograft tolerance is perforin dependent. Notably, NK cells that are perforin competent are sufficient to restore allograft tolerance in perforin-deficient recipients. Together, these results show an obligatory role for NK cells, through perforin, for induction of tolerance to islet allografts.

Note: In the version of this article initially published, the authors inadvertently misquoted a study as evidence that mouse NKT cells can express CD154 (ref. 29). Rather, the cited study concerned CD40-CD40L interactions in human NK cells. By misquoting this study, the authors also omitted an appropriate reference regarding prior evidence of CD40-CD40L interactions by murine NKT cells (Kitamura, H. et al., J. Exp. Med. 189, 1121; 1999). These errors have been corrected in the PDF version.

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Figure 1: MHC class I–deficient recipients are resistant to allograft tolerance.
Figure 2: NK1.1+ cells are required for allograft tolerance.
Figure 3: NKT cells are not required for allograft tolerance.
Figure 4: CD154-specific monoclonal antibody–induced alterations in lymphocyte populations require NK cells.
Figure 5: Perforin-competent NK cells restore tolerance in perforin-deficient (PFPKO) recipients.

Change history

  • 24 February 2006

    Note: In the version of this article initially published, the authors inadvertently misquoted a study as evidence that mouse NKT cells can express CD154 (ref. 29). Rather, the cited study concerned CD40-CD40L interactions in human NK cells. By misquoting this study, the authors also omitted an appropriate reference regarding prior evidence of CD40-CD40L interactions by murine NKT cells (Kitamura, H. et al., J. Exp. Med. 189, 1121; 1999). These errors have been corrected in the PDF version.

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Acknowledgements

We would like to thank L. Gapin for experimental advice, T. Rubtsov for technical support and M. Sleater for critical review of the manuscript.

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Correspondence to Ronald G Gill.

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Supplementary information

Supplementary Fig. 1

NK and NKT cell activity increase in animals deficient in other class I pathways. (PDF 97 kb)

Supplementary Fig. 2

Anti-CD154 treatment permits NK cell killing and NKT cell IL-4 production. (PDF 83 kb)

Supplementary Table 1

CD8 T cells are not required for anti-CD154 induced allograft tolerance. (PDF 33 kb)

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Beilke, J., Kuhl, N., Kaer, L. et al. NK cells promote islet allograft tolerance via a perforin-dependent mechanism. Nat Med 11, 1059–1065 (2005). https://doi.org/10.1038/nm1296

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