POLYMORPHIC HH GENES IN THE HLA-B(C) REGION CONTROL NATURAL-KILLER-CELL FREQUENCY AND ACTIVITY

We demonstrated earlier that individuals homozygous for conserved majo r histocompatibility complex (MHC)-wended haplotypes have low natural killer (NK) activity as measured by cytolysis of the K562 tumor cell l ine. In the present study, we investigated the segregation and MHC lin kage of NK activity in families in which MHC haplotypes of human histo compatibility leukocyte antigens (HLA)-A, -C, and -B, complotype, and DR specificities are known. In two informative families, low activity was inherited as a recessive trait linked to the MHC. By using individ uals homozygous for specific fragments of extended haplotypes or for H LA-B alleles, we found that the HLA-C and -B and not the complotype or HLA-DR region contains genes controlling NK activity. The majority of the unrelated individuals with low NK activity were homozygous or dou bly heterozygous for HLA-B7 (Cw7), B8 (Cw7), B44 (Cw5), B18, or B57 (C w6). Thus, these alleles form one complementation group designated NKB 1. Another less frequent group, NKB2, was also identified, and consist ed of individuals homozygous for B35 (Cw4). NK activity was correlated with the number of circulating NK (CD16+CD56+) cells. Individuals hom ozygous for the NKB complementation groups have fewer circulating NK c ells than individuals heterozygous for these alleles and alleles of ot her complementation groups, possibly explaining the low activity of ce lls in these subjects. These findings suggest that during the maturati on of NK cells there is NK cellular deletion in donors homozygous for NKB genes resulting in low NK cell numbers and activity.