Cre recombinase-mediated inactivation of H-2Dd transgene expression: evidence for partial missing self-recognition by Ly49A NK cells.
We have established H-2D(d)-transgenic (Tg) mice, in which H-2D(d) expression can be extinguished by Cre recombinase-mediated deletion of an essential portion of the transgene (Tg). NK cells adapted to the expression of the H-2D(d) Tg in H-2(b) mice and acquired reactivity to cells lacking H-2D(d), both in vivo and in vitro. H-2D(d)-Tg mice crossed to mice harboring an Mx-Cre Tg resulted in mosaic H-2D(d) expression. That abrogated NK cell reactivity to cells lacking D(d). In D(d) single Tg mice it is the Ly49A+ NK cell subset that reacts to cells lacking D(d), because the inhibitory Ly49A receptor is no longer engaged by its D(d) ligand. In contrast, Ly49A+ NK cells from D(d) x MxCre double Tg mice were unable to react to D(d)-negative cells. These Ly49A+ NK cells retained reactivity to target cells that were completely devoid of MHC class I molecules, suggesting that they were not anergic. Variegated D(d) expression thus impacts specifically missing D(d) but not globally missing class I reactivity by Ly49A+ NK cells. We propose that the absence of D(d) from some host cells results in the acquisition of only partial missing self-reactivity.
Ioannidis
V
V
Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.
Zimmer
J
J
Beermann
F
F
Held
W
W
D000818:Animals; D000950:Antigens, Ly; D002352:Carrier Proteins / Q000096:biosynthesis*; D002478:Cells, Cultured; D003433:Crosses, Genetic; D003587:Cytomegalovirus / Q000235:genetics; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D020868:Gene Silencing / Q000276:immunology*; D005822:Genetic Vectors / Q000138:chemical synthesis; D006183:H-2 Antigens / Q000096:biosynthesis / Q000235:genetics*; D064532:Histocompatibility Antigen H-2D; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D019426:Integrases / Q000235:genetics / Q000502:physiology*; D007694:Killer Cells, Natural / Q000201:enzymology / Q000276:immunology*; D037181:Lectins, C-Type; D016131:Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology*; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011960:Receptors, Estrogen / Q000235:genetics; D055630:Receptors, NK Cell Lectin-Like; D017384:Sequence Deletion / Q000276:immunology; D019076:Transgenes / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*
D000950:Antigens, Ly; D002352:Carrier Proteins; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D015395:Histocompatibility Antigens Class I; C527088:Klra1 protein, mouse; D037181:Lectins, C-Type; D008565:Membrane Proteins; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011960:Receptors, Estrogen; D055630:Receptors, NK Cell Lectin-Like; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases