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.