CD160 is a human natural killer (NK)-
IntroductionCD160 is an Ig-like activating natural killer (NK) cell receptor expressed on the majority of circulating NK cells and on a subset of circulating cytotoxic T cells, but not on B cells or EBV-transformed B-cell lines. 1,2 In contrast to the majority of NK cell receptor genes located on chromosomes 12 and 19, 3 the CD160 gene is located on chromosome 1q42.3. 4 CD160 is expressed by most peripheral blood TCR␥␦ lymphocytes, a minor subset of circulating CD8 brightϩ TCR␣ cells, and all small intestinal intraepithelial T lymphocytes, phenotyped as CD3 ϩ TCR␣/  ϩ CD56 Ϫ . 5 A minor population of CD4 ϩ T cells also express CD160. 6 CD160 mRNA expression was shown to be highly restricted to NK cells and not detected in myeloid and B-cell lines by Northern blot analysis. 5 Outside of the immune system, CD160 is expressed on endothelial cells of neoangiogenic microvessels at the periphery of tumors. 7 NK cells play a key role in innate immunity, having potent cytolytic activity against virally infected and tumor cells. 8 NK-cell activity is regulated by inhibitory and activatory receptors expressed at the cell surface and their interaction with associated ligands. 9 CD160 binds to MHC class Ia and Ib with low affinity 10 and triggers cytotoxic function in peripheral blood NK cells, as well as cytokine production, including IFN-␥, TNF-␣, and 12 Only a limited number of human activating NK-cell receptors have been demonstrated to induce cytokine production and release in addition to cytotoxicity. 13 The PI3K signaling molecule is required for CD160-mediated cytokine release, with involvement of the signaling molecules Syk and ERK upstream and downstream of PI3K, respectively. 14 Recent work has demonstrated CD160 expression in malignant human B cells. 15 CD160 expressed on the surface of B-cell chronic lymphocytic leukemia (CLL) mimicked CD160 functions in normal NK and T cells: cellular activation, up-regulation of BCL-2 and BCL-XL , and improved in vitro cell survival and cytokine production, specifically IL-6 and IL-8. PI3K/Akt signaling was required for CD160-mediated functions in CLL cells. 15 Similar "aberrant" expression of a signaling molecule, CD3-receptor-associated protein tyrosine kinase or -associated protein-70 (ZAP-70), was reported in CLL. 16,17 Like CD160, ZAP-70 was initially described exclusively in T cells and NK cells, 18 but was subsequently detected in mature and immature human B-lymphoid malignancies, 19-21 as well as normal murine and human B cells. 22,23 In the present study, we investigated normal and malignant human B cells for expression of CD160. This extensive study established that the NK cell receptor antigen CD160 shows restricted expression in the B-cell lineage to malignant compared with normal B cells. Moreover, the varying expression of CD160 can be exploited diagnostically, as shown in test and validation sets consisting of Ͼ 970 cases of B-cell lymphoproliferative disorders (B-LPDs).
Methods
Patients and samplesThis study involved a t...