Xenogeneic β2-Microglobulin Substitution Alters NK Cell Function

• Published in: The Journal of immunology (1950) 2007-08, Vol.179 (3), p.1466-1474
• Main Authors: Benoît, Loralyn A., Tan, Rusung
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.179.3.1466

Recently, it has been shown that human β2-microglobulin (h-β2m) blocks the association between the NK cell inhibitory receptor Ly49C and H-2Kb. Given this finding, we therefore sought to assess the immunobiology of NK cells derived from C57BL/6 (H-2b) mice expressing exclusively h-β2m. Initial analysis revealed that the Ly49C expression profile of NK cells from h-β2m+ mice was modified, despite the fact that H-2Kb expression was normal in these mice. Moreover, the NK cells were not anergic in that IL-2 treatment of h-β2m+ NK cells in vitro enabled efficient lysis of prototypic tumor cell lines as well as of syngeneic h-β2m+ lymphoblasts. This loss of self-tolerance appeared to correlate with the activation status of h-β2m+ NK cells because quiescent h-β2m+ transplant recipients maintained h-β2m+ grafts but polyinosine:polycytidylic acid-treated recipients acutely rejected h-β2m+ grafts. NK cell reactivity toward h-β2m+ targets was attributed to defective Ly49C interactions with h-β2m:H-2Kb molecules. With regard to NK cell regulatory mechanisms, we observed that h-β2m:H-2Kb complexes in the cis-configuration were inefficient at regulating Ly49C and, furthermore, that receptor-mediated uptake of h-β2m:H-2Kb by Ly49C was impaired compared with uptake of mouse β2m:H-2Kb. Thus, we conclude that transgenic expression of h-β2m 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.