TNFR-Associated Factor 6 and TGF-β–Activated Kinase 1 Control Signals for a Senescence Response by an Endosomal NK Cell Receptor

Abstract

The endosomal innate receptor CD158d (KIR2DL4) induces cellular senescence in human NK cells in response to soluble ligand (HLA-G or agonist antibody). These senescent NK cells display a senescence-associated secretory phenotype (SASP) and their secretome promotes vascular remodeling and angiogenesis. To understand how CD158d initiates signaling for a senescence response, we mapped the region in its cytoplasmic tail that controls signaling. We identified a conserved TRAF6 binding motif, which was required for CD158d-induced NF-κB activation and IL-8 secretion, for TRAF6 association with CD158d, and for TRAF6 recruitment to CD158d+ endosomes in transfected cells. The adaptor TRAF6 is known to couple proximal signals from receptors such as endosomal TLRs and CD40 through the kinase TAK1 for NF-κB-dependent pro-inflammatory responses. siRNA-mediated silencing of TRAF6 and TAK1, and inhibition of TAK1 blocked CD158d-dependent IL-8 secretion. Stimulation of primary, resting NK cells with soluble Ab to CD158d induced TRAF6 association with CD158d, induced TAK1 phosphorylation, and inhibition of TAK1 blocked the CD158d-dependent reprogramming of NK cells that produces the SASP signature. Our results reveal that a prototypic TLR and TNF-receptor signaling pathway is used by a killer cell immunoglobulin-like receptor that promotes secretion of pro-inflammatory and pro-angiogenic mediators as part of a unique senescence phenotype in NK cells.

Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions

“…The arrest of cell proliferation caused by an increase in the expression of cell cycle inhibitors, such as p16INK4a, p21WAF1, and p53, is a typical alteration encountered both in senescent immune and non-immune cells of mice and humans. For instance, these changes are present in senescent T cells [ 49 – 51 ], B cells [ 31 ], NK cells [ 52 ], and macrophages [ 53 – 55 ]. Cell cycle arrest is commonly associated with the increased expression of senescence-associated β-galactosidase (SA-β-gal) and heterochromatin foci (SAHF) [ 52 – 54 , 56 , 57 ] as well as the shortening of telomeres [ 58 – 60 ].…”

Cellular senescence impact on immune cell fate and function

“…This senescence occurs upon activation of the NK receptor, CD158d, by the soluble HLA‐G, a nonclassical major histocompatibility complex molecule, secreted by fetal trophoblasts. In turn, senescent NK cells produce a specific SASP that positively regulates the neo‐angiogenesis required for embryo implantation during the first trimester of pregnancy (Rajagopalan & Long, 2012; Rajagopalan et al ., 2014). These findings highlight a positive role of cellular senescence in a physiological immune context and open new perspectives in the NK field.…”

HLA-G-mediated NK cell senescence promotes vascular remodeling: implications for reproduction

“…Its association with TNF-receptor-associated factor 6 results in phosphorylation of the kinase TAK1 and links it to nuclear factor kappa B activation pathways. 50 The ubiquitin ligase TNF-receptor-associated factor 6 is known to couple proximal signals from endosomal receptors, such as the Toll-like receptors, through TAK1 for nuclear factor kappa B-dependent pro-inflammatory responses. In this way, KIR2DL4 activates nuclear factor kappa B responses via the canonical pathway to generate pro-inflammatory/pro-angiogenic signals.…”