HOXB CLUSTER GENES IN ACTIVATED NATURAL-KILLER LYMPHOCYTES EXPRESSIONFROM 3'-]5'-CLUSTER SIDE AND PROLIFERATIVE FUNCTION

The expression of HOXB cluster genes (i.e., B7 through B9) was evaluat ed in purified IL-2/1L-1 beta B-activated NK lymphocytes from normal a dult peripheral blood by RNase protection and reverse transcription-PC R. In quiescent NK cells these genes are essentially not expressed. Af ter lL-2/lL-1 beta addition, we observed a coordinate induction wave i n the 3'-->5' HOXB cluster direction, i.e., from B1 through B9. As not able exceptions, B8 is silent, while B9 RNA is detected starting from 6 h through day 11. Furthermore, the 3' located B2/B3/B4 are expressed earlier and at higher level than the 5' located B5/B6/B7/B8. In lL-2/ IL-1 beta-activated NK cells, treatment with antisense oligonucleotide s targeting B2 mRNA causes a significant inhibition of both cell proli feration and expression of activation markers (i.e., IL-2R alpha-chain and transferrin receptor). These studies provide novel evidence of th e role of HOX genes in adult NK cell proliferation. Thus, 1) a coordin ate activation of HOXB genes from the 3'-->5' cluster side apparently underlies Ib-2/IL-1 beta-induced NK cell activation. 2) Since NK cell activation and survival induced by IL-12 and c-kif ligand, respectivel y, are not associated with cell proliferation of HOXB gene expression, it is apparent that HOXB gene induction is specifically associated wi th IL-2-induced NK cell proliferation. 3) Studies with antisense oligo mer targeting HOXB2 mRNA suggest an important role for B2 in NK cell p roliferation, possibly in part via the IL-2R.