An autosomal dominant locus, Nka, mapping to the Ly-49 region of a rat natural killer (NK) gene complex, controls NK cell lysis of allogeneic lymphocytes

Abstract

Natural Killer (NK) cells can recognize and kill MHC-incompatible normal bone marrow-derived calls. Presently characterized MHC-binding receptors on NK cells, including the Ly-49 family m the mouse, transmit inhibitory signals upon binding to cognate class 1 MHC ligands. Here we study in vivo NK- mediated lysis of normal allogeneic lymphocytes in crosses between alloreactivity-competent PVG rats and alloreactivity-deficient DA rats. NK cells from both strains are able to lyse standard tumor targets. We identify an autosomal dominant locus, Nka, that controls NK-mediated alloreactivity. Individuals carrying the dominant PVG allele in single dose were fully competent in eliminating allogeneic target cells, suggesting that Nka encodes or regulates a gone product inducing or activating alloreactivity. By linkage analysis and pulsed field gel electrophoresis, a natural killer gene complex (NKC) on rat chromosome 4 is described that contains the rat NKR-P1 and Ly- 49 multigene families plus a rat NKG2D homologue.Nka maps within the NKC, together with the most telomeric Ly-49 family members, but separate from NKG2D and the NKP-P1 family. The Nka-encoded response, moreover, correlates with the expression of transcripts for Ly-49 receptors in NK cell populations, as Northern blot analysis demonstrated low expression of Ly-49 genes in DA NK cells, in contrast to high expression ill alloreactivity competent PVG, (DA x PVG)F1, and PVG.1AV1 NK cells. The low Ly-49 expression in DA is not reduced by MHC haplotype, as demonstrated by high expression of Ly-49 in the DA MHC-congenic PVG.1AV1 strain. Finally, we have cloned and characterized the first four members of the rat Ly-49 gone family. Their cytoplasmic domains demonstrate substantial heterogeneity, consistent with the hypothesis that different Ly-49 family members may subserve different signaling functions.