title: NK cells promote islet allograft tolerance via a perforin-dependent mechanism.
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.
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, 1775 Ursula Street, Box B-140, Aurora, Colorado 80010, USA.
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Beilke
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Kuhl
authors.forename: Luc
authors.initials: L
authors.lastname: Van Kaer
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Gill
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D040881:CD11a Antigen / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007167:Immunotherapy; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D018448:Models, Immunological; D054353:Perforin; D010641:Phenotype; D052899:Pore Forming Cytotoxic Proteins; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D040881:CD11a Antigen; D019013:CD40 Antigens; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand