Murine NK cell allospecificity-1 is defined by inhibitory ligands

Hemopoietic allografts of normal and neoplastic origin are subject to NK cell-mediated resistance in mice. Susceptibility to this resistance is controlled by MHC-linked genes in a recessive manner. Several distinct specificities could be postulated to explain the strain-dependent pattern of resistance. These presumptive specificities for recognition are H-2 haplotype dependent, but the correspondence is not one-to-one. For example, resistance of H-2(d) or H-2(b/d) host to H-2^b graft operationally defines specificity- 1, establishing its link with haplotype H-2^b. To examine the molecular basis of specificity-1, spontaneous D(d)-loss mutant clones were isolated from H- 2(b/d) and H-2(d) hemopoietic cell lines, i.e., 416B of (C57BL/6 x DBA/2)F₁ (B6D2F₁) origin and L1210 of DBA/2 origin, both of which lack specificity- 1. The expression of specificity-1 in the mutant clones was examined in vivo and in vitro. The results indicate that D(d)-loss clones of 416B and L1210 lines express specificity-1. These data suggest that murine NK cell allospecificity-1 is defined primarily by the absence of the D(d) molecule or other class I molecules sharing the protective motifs; no H-2^b-associated genes play a relevant role. This conclusion is consistent with the missing self hypothesis of NK cell reactivity, and is in agreement with the observation that lysis of B6 targets by B6D2F₁ NK cells is mediated mostly by cells that express Ly-49A and/or Ly-49G2.