Analysis of NK cell/DC interaction in NK-type lymphoproliferative disease of granular lymphocytes (LDGL): role of DNAM-1 and NKp30

Objective: Natural killer (NK) cells and dendritic cells (DC) can give rise to reciprocal functional interactions resulting in promotion of DC maturation, killing of immature DC (iDC), and proliferation of NK cells. In this study, we analyze whether, in NK-lymphoproliferative disease of granular lymphocytes (LDGL) patients, this function could be altered and contribute to the persistence of the disease. Materials and Methods: Freshly isolated peripheral blood NK granular lymphocytes (GL) and NK cell lines derived from 13 different NK-LDGL patients were analyzed in coculture experiments to evaluate their ability to interact with monocyte-derived DCs (Mo-DC). Results: As compared to NK cells isolated from healthy donors, NK-GLs displayed, in most cases, a reduced capability of promoting Mo-DC maturation and of killing iDC. These findings could be explained, at least in part, by the low expression levels of NKp30: an activating receptor involved in the molecular interactions occurring between NK cells and DC. We also show that, in the presence of DC-derived cytokines such as interleukin-12, in both patients and healthy individuals, DNAM-1 can cooperate with NKp30 to induce NK cells to kill DC, release tumor necrosis factor - α, and promote DC maturation. This contribution, however, is not sufficient to compensate for the defect in patients' NK cells. Conclusion: Besides expanding knowledge of the molecular basis of the NK/DC cross-talk, our study demonstrates that NK cells from NK-LDGL patients are impaired in their ability to interact with Mo-DC. The possible relationship between such abnormal NK cell/DC interactions and chronic NK cell proliferation are discussed.