CD16/FcãRIII Antigen Expression Determines Oxidative Sensitivity in Cytotoxic Lymphocyte Subsets

Oxidative stress, referring to cellular toxicity induced by reactive oxygen metabolites (ROM), has been proposed as a mechanism of immunosuppression in hematological malignant diseases. ROM produced by myeloid cells such as normal or malignant phagocytes have been shown to compromise functions of lymphocytes including natural killer (NK) cells and CD4+ or CD8+ T cells. Phagocyte-derived ROM induce downmodulation of the CD3/CD16 zeta; transduction antigen in these lymphocyte subsets with ensuing loss of function and lack of responsiveness to activating cytokines such as IL- 2. In addition, ROM exposure triggers poly(ADP-ribose) polymerase 1- and apoptosisinducing factor-dependent apoptosis in NK and T cells, but the molecular details of the ROM/lymphocyte interaction are not fully understood. The present study sought to determine the role of the CD16/FcγRIII (CD16) antigen, a signal transduction molecule expressed by NK and T cells and a receptor for the Fc portion of IgG, for oxidative stress in lymphocytes. Human NK (CD56+) or T cells (CD4+ or CD8+) were sorted into pure (>99%) CD16+ or CD16− populations, and incubated overnight with ROM-producing autologous mononuclear phagocytes or exogenous hydrogen peroxide. For all subsets of lymphocytes, the expression of CD16 was a strong determinant of the propensity of cells to acquire features of apoptosis after ROM exposure, as reflected by a pronounced difference of ROM sensitivity between CD16+ and CD16− NK or T cell populations. The higher degree of ROM-induced apoptosis in the CD16+ subsets was observed regardless of whether lymphocytes were incubated with autologous mononuclear phagocytes or exposed to exogenous hydrogen peroxide (p=0.04–0.001 for CD4+/16+, CD8+/16+ and CD16+/56+ lymphocytes as compared with corresponding CD16− subsets). Similar experiments using unsorted T and NK cells suggested that the differential sensitivity to oxidative stress in CD16+ and CD16− lymphocyte subsets was not explained by anti- CD16/CD16 interaction. In conclusion, our findings imply that oxidant-induced apoptosis is preferentially induced in lymphocytes expressing the CD16/FcγRIII antigen.