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Transplantation of Pancreatic Islets Into the Kidney Capsule of Diabetic Mice
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NK cells promote islet allograft tolerance via a perforin-dependent mechanism

Joshua N Beilke1, Nathan R Kuhl, Luc Van Kaer

  • 1Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, 1775 Ursula Street, Box B-140, Aurora, Colorado 80010, USA.

Nature Medicine
|September 13, 2005
PubMed

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.

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