Ly49I NK cell receptor transgene inhibition of rejection of H2b mouse bone marrow transplants

The Ly49 family of genes encode NK cell receptors that bind class I MHC Ags and transmit negative signals if the cytoplasmic domains have immunoregulatory tyrosine-based inhibitory motifs (ITIMs). 5E6 mAbs recognize Ly49C and Ly49I receptors and depletion of 5E6(+) NK cells prevents rejection of allogeneic or parental-strain H2(d) bone marrow cell (BMC) grafts. To determine the function of the Ly49I gene in the rejection of BMC grafts, we transfected fertilized eggs of FVB mice with a vector containing DNA for B6 strain Ly49I (Ly49I(B6)). Ly49I(B6) is ITIM+ and is recognized by 5E6 as well as Ly49I-specific 8H7 mAbs. Normal FVB H2(q) mice reject H2(b) but not H2(d) BMC allografts, and the rejection of H2(b) BMC was inhibited partially by anti-NK1.1 and completely by anti-asialo GM1, but not by anti-CD8, Abs. In FVB mice, NK1.1 is expressed on only 60% NK cells. FVB.Ly49I(B6) hosts failed to reject H2(d) or H2(b) BMC, but did reject class I-deficient TAP-1(-/-) BMC, indicating that NK cells were functional. Nondepleting doses of anti-Ly49I Abs reversed the acceptance of H2(b) BMC by FVB.Ly49I(B6) mice. FVB.Ly49I(B6+/-) mice were crossed and back-crossed with 129 mice-H2(b), 5E6(-), poor responders to H2(d) BMC grafts. While transgene-negative H2(b/q) F-1 or first-generation back-crossed mice rejected H2(b) marrow grafts (hybrid resistance), transgene-positive mice did not. Thus B6 strain Ly49I receptors transmit inhibitory signals from H2(b) MHC class I molecules. Moreover, Ly49IB6 has no positive influence on the rejection of H2(d) allografts.