title: Beta2-microglobulin-deficient NK cells show increased sensitivity to MHC class I-mediated inhibition, but self tolerance does not depend upon target cell expression of H-2Kb and Db heavy chains.
abstract: Mice lacking beta2-microglobulin (beta2m- mice) express greatly reduced levels of MHC class I molecules, and cells from beta2m- mice are therefore highly sensitive to NK cells. However, NK cells from beta2m- mice fail to kill beta2m- normal cells, showing that they are self tolerant. In a first attempt to understand better the basis of this tolerance, we have analyzed more extensively the target cell specificity of beta2m- NK cells. In a comparison between several MHC class I-deficient and positive target cell pairs for sensitivity to beta2m- NK cells, we made the following observations: First, beta2m- NK cells displayed a close to normal ability to kill a panel of MHC class I-deficient tumor cells, despite their nonresponsiveness to beta2m- concanavalin A (Con A)-activated T cell blasts. Secondly, beta2m- NK cells were highly sensitive to MHC class I-mediated inhibition, in fact more so than beta2m+ NK cells. Thirdly beta2m- NK cells were not only tolerant to beta2m- Con A blasts but also to Con A blasts from H-2Kb-/Db- double deficient mice in vitro. We conclude that NK cell tolerance against MHC class I-deficient targets is restricted to nontransformed cells and independent of target cell expression of MHC class I free heavy chains. The enhanced ability of beta2m- NK cells to distinguish between MHC class I-negative and -positive target cells may be explained by increased expression of Ly49 receptors, as described previously. However, the mechanisms for enhanced inhibition by MHC class I molecules appear to be unrelated to self tolerance in beta2m- mice, which may instead operate through mechanisms involving triggering pathways.
authors.affiliation: Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden. Petter.Hoglund@mtc.ki.se
authors.forename: P
authors.initials: P
authors.lastname: Höglund
authors.forename: R
authors.initials: R
authors.lastname: Glas
authors.forename: C
authors.initials: C
authors.lastname: Ménard
authors.forename: A
authors.initials: A
authors.lastname: Kåse
authors.forename: M H
authors.initials: MH
authors.lastname: Johansson
authors.forename: L
authors.initials: L
authors.lastname: Franksson
authors.forename: F
authors.initials: F
authors.lastname: Lemmonier
authors.forename: K
authors.initials: K
authors.lastname: Kärre
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D003208:Concanavalin A / Q000494:pharmacology; D003433:Crosses, Genetic; D003602:Cytotoxicity, Immunologic; D005805:Genes, MHC Class I; D006183:H-2 Antigens / Q000276:immunology*; D064532:Histocompatibility Antigen H-2D; D007371:Interferon-gamma / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins; D017634:Self Tolerance / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects; D014407:Tumor Cells, Cultured; D001613:beta 2-Microglobulin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D064532:Histocompatibility Antigen H-2D; D011994:Recombinant Proteins; D001613:beta 2-Microglobulin; D003208:Concanavalin A; D007371:Interferon-gamma