RECOGNITION OF HUMAN HISTOCOMPATIBILITY LEUKOCYTE ANTIGEN (HLA)-E COMPLEXED WITH HLA CLASS-I SIGNAL SEQUENCE-DERIVED PEPTIDES BY CD94 NKG2 CONFERS PROTECTION FROM NATURAL-KILLER CELL-MEDIATED LYSIS/

Human histocompatibility leukocyte antigen (HLA)-E is a nonclassical H LA class I molecule, the gene for which is transcribed in most tissues . It has recently been reported that this molecule binds peptides deri ved from the signal sequence of HLA class I proteins; however, no func tion for HLA-E has yet been described. We show that natural killer (NK ) cells can recognize target cells expressing HLA-E molecules on the c ell surface and this interaction results in inhibition of the lytic pr ocess. Furthermore, HLA-E recognition is mediated primarily through th e CD94/NKG2-A heterodimer, as CD94-specific, but not killer cell inhib itory receptor (KIR)-specific mAbs block HLA-E-mediated protection of target cells. Cell surface HLA-E could be increased by incubation with synthetic peptides corresponding to residues 3-11 from the signal seq uences of a number of HLA class I molecules; however, only peptides wh ich contained a Met at position 2 were capable of conferring resistanc e to NK-mediated lysis, whereas those having Thr at position 2 had no effect. Interestingly, HLA class I molecules previously correlated wit h CD94/NKG2 recognition all have Met at residue 4 of the signal sequen ce (position 2 of the HLA-E binding peptide), whereas those which have been reported not to interact with CD94/NKG2 have Thr at this positio n. Thus, these data show a function for HLA-E and suggest an alternati ve explanation for the apparent broad reactivity of CD94/NKG2 with HLA class I molecules; that CD94/NKG2 interacts with HLA-E complexed with signal sequence peptides derived from ''protective'' HLA class I alle les rather than directly interacting with classical HLA class I protei ns.