NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17)

Abstract

• Activated NK cells loose CD16 (FcRgIII) and CD62L through a metalloprotease called ADAM17. • Inhibition of ADAM17enhances CD16 mediated NK cell function by preserving CD16 on the NK cell surface to enhance ADCC.The Fc receptor CD16 is present on essentially all CD56 dim peripheral blood natural killer (NK) cells. Upon recognition of antibody-coated cells it delivers a potent signal to NK cells, which eliminate targets through direct killing and cytokine production. Here we investigated the regulation of CD16 surface expression after NK cell activation. Cytokine activation and target cell stimulation led to marked decreases in CD16 expression. Activation of CD56 dim NK cells by cross-linking CD16 with antibodies resulted in a loss of CD16 and CD62L, which correlated with increased interferon-g production. A disintegrin and metalloprotease-17 (ADAM17) is shown to be expressed by NK cells, and its selective inhibition abrogated CD16 and CD62L shedding, and led to enhanced interferon-g production, especially when triggering was delivered through CD16. Fc-induced production of cytokines by NK cells exposed to rituximab-coated B cell targets was also enhanced by ADAM17 inhibition. This supports an important role for targeting ADAM17 to prevent CD16 shedding and improve the efficacy of therapeutic antibodies. Our findings demonstrate that over-activation of ADAM17 in NK cells may be detrimental to their effector functions by down-regulating surface expression of CD16 and CD62L. (Blood. 2013;121(18):3599-3608)

Phenotypical and functional profiles of natural killer cells exhibiting matrix metalloproteinase-mediated CD16 cleavage after anti-HIV antibody-dependent activation

“…These data have been interpreted previously as NK cell ADCC competency associating with slower progression to AIDS. It should be noted, however, that a large body of literature now exists demonstrating that activation of NK cells results in decreased CD16 surface expression and functional anergy [14][15][16][17]. Thus, activation of NK cells to mediate ADCC might itself induce phenotypical and functional alterations in NK cells that are similar to those associated with progression to AIDS.…”

“…Furthermore, post-activation decreases in CD16 expression are induced by matrix metalloproteinases (MMP) that are produced in NK cells upon activation. The ADAM17 MMP has been implicated in cleaving CD16 from the surface of NK cells activated by cytokines, as well as antibody-dependent and -independent stimuli [17].…”

Multifunctional human CD56low CD16low natural killer cells are the prominent subset in bone marrow of both healthy pediatric donors and leukemic patients

“…48,49 Moreover, CD16 loss is also associated with downregulation of CD62L expression, this being attributable to the activation of the metalloprotease ADAM17. 48 low NK-cell subset.…”

Donor Natural Killer Cells and Their Therapeutic Potential in Allogeneic Hematopoietic Stem Cell Transplantation

“…The preclinical results demonstrated these antibodies appear safe and do not induce autoimmunity [175]. Additionally, a disintegrin and metalloprotease-17 (ADAM17) was demonstrated to induce activated NK cells to lose expression of CD16 and CD62L [176]. Therefore, pharmacologic inhibition of ADAM17 is used to enhance the cytotoxicity of NK cells toward Rituximab bound lymphoma cells.…”