title: Xenogeneic beta 2-microglobulin substitution alters NK cell function.
abstract: Recently, it has been shown that human beta(2)-microglobulin (h-beta(2)m) blocks the association between the NK cell inhibitory receptor Ly49C and H-2K(b). Given this finding, we therefore sought to assess the immunobiology of NK cells derived from C57BL/6 (H-2(b)) mice expressing exclusively h-beta(2)m. Initial analysis revealed that the Ly49C expression profile of NK cells from h-beta(2)m(+) mice was modified, despite the fact that H-2K(b) expression was normal in these mice. Moreover, the NK cells were not anergic in that IL-2 treatment of h-beta(2)m(+) NK cells in vitro enabled efficient lysis of prototypic tumor cell lines as well as of syngeneic h-beta(2)m(+) lymphoblasts. This loss of self-tolerance appeared to correlate with the activation status of h-beta(2)m(+) NK cells because quiescent h-beta(2)m(+) transplant recipients maintained h-beta(2)m(+) grafts but polyinosine:polycytidylic acid-treated recipients acutely rejected h-beta(2)m(+) grafts. NK cell reactivity toward h-beta(2)m(+) targets was attributed to defective Ly49C interactions with h-beta(2)m:H-2K(b) molecules. With regard to NK cell regulatory mechanisms, we observed that h-beta(2)m:H-2K(b) complexes in the cis-configuration were inefficient at regulating Ly49C and, furthermore, that receptor-mediated uptake of h-beta(2)m:H-2K(b) by Ly49C was impaired compared with uptake of mouse beta(2)m:H-2K(b). Thus, we conclude that transgenic expression of h-beta(2)m alters self-MHC class I in such a way that it modulates the NK cell phenotype and interferes with regulatory mechanisms, which in turn causes in vitro-expanded and polyinosine:polycytidylic acid-activated NK cells to be partially self-reactive similar to what is seen with NK cells derived from MHC class I-deficient mice.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Loralyn A
authors.initials: LA
authors.lastname: Benoît
authors.forename: Rusung
authors.initials: R
authors.lastname: Tan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005260:Female; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology; D001613:beta 2-Microglobulin / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*
chemical_list: D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D001613:beta 2-Microglobulin