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

Beilke JN, Kuhl NR, Van Kaer L, Gill RG
Nat Med. 2005 11 (10): 1059-65

PMID: 16155578 · DOI:10.1038/nm1296

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.

MeSH Terms (23)

Animals Antibodies, Monoclonal CD8-Positive T-Lymphocytes CD11a Antigen CD40 Antigens CD40 Ligand Graft Survival Histocompatibility Antigens Class I Immune Tolerance Immunotherapy Intercellular Adhesion Molecule-1 Islets of Langerhans Transplantation Killer Cells, Natural Major Histocompatibility Complex Membrane Glycoproteins Mice Mice, Knockout Models, Animal Models, Immunological Perforin Phenotype Pore Forming Cytotoxic Proteins Transplantation, Homologous

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