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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We would like to thank L. Gapin for experimental advice, T. Rubtsov for technical support and M. Sleater for critical review of the manuscript.
The authors declare no competing financial interests.
NK and NKT cell activity increase in animals deficient in other class I pathways. (PDF 97 kb)
Anti-CD154 treatment permits NK cell killing and NKT cell IL-4 production. (PDF 83 kb)
CD8 T cells are not required for anti-CD154 induced allograft tolerance. (PDF 33 kb)
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