Increased expression of non-functional killer inhibitory receptor CD94 in CD8(+) cells of myeloma patients

Different MHC class I-specific killer inhibitory receptors (KIRs) are expre ssed in vivo by a minor fraction of activated memory CD8(+) cells. It has b een postulated that KIRs may 'fine-tune' specific responses by altering the ir threshold of activation by the TCR-CD3 complex. We have previously shown that, in multiple myeloma (MM) patients, a large fraction of peripheral bl ood CD8(+) cells display the phenotype of chronically activated memory T ce lls (CD38(+), HLA-DR+, CD25(-), CD45R0(+), CD28(-)). We investigated the ex pression of KIRs on MM T cells and determined their possible influence on c ytolytic responses elicited via the CD3-TCR complex. The expression of CD94 , a molecule that is part of a heterodimeric KIR recognizing the nonclassic al MHC surface HLA-E molecule, was almost threefold higher in MM T cells th an in age-matched normal control subjects (P < 0.0001). CD94 expression was preferentially confined to CD8(+) cells but not restricted to activated (H LA-DR+) and/or memory (CD45R0(+)) T cells. Unlike normal T cells, in which CD94 is assembled with glycoproteins of the NKG2 family to form functional receptors with activating or inhibitory properties, most CD94(+) MM T cells were devoid of both the NKG2-A and NKG2-C glycoproteins detected in the in hibitory or activating form respectively. CD94 blockade did not significant ly affect either T-cell proliferation or cytotoxic T-lymphocyte generation induced by the myeloma-derived cell lines NCI and RPMI 8226. Similarly, the cytolytic activity induced by direct anti-CD3-mediated targeting of MM T c ells to FCR+ P815 target cells was unaffected by the addition of anti-CD94 and/or anti-NKG2-A/C monoclonal antibodies (mAbs). These data indicate that the large majority of MM CD8(+) cells do not express a functional CD94 rec eptor. Thus, their ability to 'fine-tune' an appropriate immune response ag ainst tumour cells can be impaired.