ADAM17 regulates NK cell production of IL-10 and drives of NK cell “helper” function through the activation of TNFa 4631

Abstract Description The natural killer (NK) cell repertoire is often skewed by HIV and CMV co-infection, characterized by an inflated rare CD16+/FcRγ- “memory-like” population with potent antibody-mediated cytolytic ability. However, these NK cells display limited responsiveness to IL-18, as they fail to downregulate CD16 expression and differentiate into cytokine producing CD83+/CCR7+ NK “helper” cells. Here, we show that ADAM17, a transmembrane protease responsible for the IL-18-induced cleavage of CD16, also regulates NK cell production of the suppressive factor IL-10, mediated through enhancement of TNFα production. When co-stimulated with IL-18 and IL-12 along with an ADAM17 inhibitor, NK cells maintained their surface expression of CD16, produced substantially less TNFα, and increased their production of IL-10 as determined by multiplex (MSD) ELISA and supported by single-cell RNA sequencing analysis. Treatment with the ADAM17 inhibitor also negatively impacted the “helper” function of the NK cells, diminishing their ability to induce dendritic cell (DC) maturation based on surface expression of CD86 and CD83, while greatly enhancing DC expression of Siglec-1 (CD169). While these findings implicate ADAM17 as regulator of NK cell IL-10 production and a driver of their “helper” function, it is unclear if the lack of ADAM17 function found among the CD16+/FcRγ- “memory-like” NK cells expanded in HIV infection translates into an enhancement in their IL-10 suppressive activity. Funding Sources Supported by NIH/NIAID R01AI152655; NIH/NHLBI U01HL146208; NIH/NIAID 2P30AI036219-26A1 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)