Possible role of natural killer cells in negative selection of mutant lymphocytes that fail to express the human leukocyte antigen-A2 allele

Increased frequencies of cells carrying mutations at several loci have been found in the blood cells of atomic-bomb (A-bomb) survivors upon testing fo ur or five decades after the bombing. Interestingly, though, we have been u nable to demonstrate any radiation-associated increases in the frequencies of mutant blood cells in which human leukocyte antigen (HLA)-A expression h as been disrupted; this is true both of preliminary rests on the T cells of a small subset of A-bomb survivors and of the much more extensive study re ported here in which we screened a much larger group of survivors for HLA-A 2 loss mutations in B cells and granulocytes as well as in T cells. In atte mpting to explain our inability to detect any increases in HLA-A2-negative cell numbers in HLA-AZ heterozygous individuals exposed to A-bomb irradiati on, we decided to test the hypothesis that HLA-A mutant lymphocytes might w ell have been induced by radiation exposure in much the same way as every o ther type of mutant we encountered, but may subsequently have been eliminat ed by the strong negative selection associated with their almost inevitable exposure to autologous natural killer (NK) cells in the bloodstream of eac h of the individuals concerned. We now report that mutant B lymphocyte cell lines that have lost the ability to express the HLA-A2 antigen do indeed a ppear to be much more readily eliminated than their parental heterozygous c ounterparts during co-culture in vitro with autologous NK cells. We make th is claim first because we have observed that adding autologous NK cells to in vitro cultures of HLA-A2 heterozygous B or T cell lines appeared to caus e a dose-dependent decrease in the numbers of HLA-A2-negative mutants that could be detected over a period of 3 days, and second because when we used peripheral blood HLA-A2 heterozygous lymphocyte cultures from which most of the autologous NK cells had been removed we found that we were able to det ect newly-arising HLA-A2 mutant T cells in substantial numbers. Taken toget her, these results strongly support the hypothesis that autologous NK cells are responsible for eliminating mutant lymphocytes that have lost the abil ity to express self-HLA class I molecules in vivo, and may well therefore e xplain why we have been unable to detect increased frequencies of HLA-A2 mu tants in samples from any of the 164 A-bomb survivors whose HLA-A2 heterozy gote status made their lymphocytes suitable for our tests, (C) 2001 Elsevie r Science B,V. All rights reserved.