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Cre Recombinase-Mediated Inactivation of H-2D^d Transgene Expression: Evidence for Partial Missing Self-Recognition by Ly49A NK Cells¹

Vassilios Ioannidis^*, Jacques Zimmer^*, Friedrich Beermann and Werner Held^2,*

^* Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland; and Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland

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.

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