Differential effects of the rejection of bone marrow allografts by the depletion of activating versus inhibiting Ly-49 natural killer cell subsets

Natural killer cells mediate the specific rejection of bone marrow cell (BMC) allografts in lethally irradiated mice. The Ly-49 family of molecules present on subsets of murine NK cells appears capable of binding class I MHC molecules, resulting in transmission of an inhibitory signal to the NK cell. These Ly-49 family members have been shown to have an immunoreceptor tyrosine-based inhibitory motif that is responsible for the inhibitory signal. However, a new Ly-49 family member was found that lacks this motif, Ly-49D, and evidence suggests that this may be an activating receptor. We therefore compared the role of the activating Ly-49 member with NK cells bearing inhibitory Ly-49 receptors in BMC rejection. Depletion of Ly-49D⁺ NK cells in H-2^b mice abrogated their ability to reject H-2(d) BMC allografts. Similarly, Ly-49C⁺ NK cells also were shown to mediate the specific rejection of H-2(d) BMC. When both subsets were depleted, an additive enhancement of BMC engraftment was observed, indicating that both subsets play a role in the rejection of allogeneic H-2-homozygous H-2(d) BMC. However, rejection of H-2(b x d) or D8 (H-2^b, D(d) transgene) BMC allografts was unaffected by Ly-49C⁺ NK cell depletion in H-2^b mice. In marked contrast, depletion of Ly-49D⁺ NK cells in H-2^b mice totally abrogated the rejection of H-2(b x d) heterozygous BMC in support of in vitro data suggesting that Ly-49D⁺ NK cells receive activating signals. Therefore, NK subsets demonstrate a differential ability to reject H-2 homozygous and heterozygous BMC.