Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling

Abstract

Natural killer (NK) cells, which have an essential role in immune defense, also contribute to reproductive success. NK cells are abundant at the maternal-fetal interface, where soluble HLA-G is produced by fetal trophoblast cells during early pregnancy. Soluble HLA-G induces a proinflammatory response in primary, resting NK cells on endocytosis into early endosomes where its receptor, CD158d, resides. CD158d initiates signaling through DNA-PKcs, Akt, and NF-κB for a proinflammatory and proangiogenic response. The physiological relevance of this endosomal signaling pathway, and how activation of CD158d through soluble ligands regulates NK cell fate and function is unknown. We show here that CD158d agonists trigger a DNA damage response signaling pathway involving cyclindependent kinase inhibitor p21 expression and heterochromatin protein HP1-γ phosphorylation. Sustained activation through CD158d induced morphological changes in NK cell shape and size, and survival in the absence of cell-cycle entry, all hallmarks of senescence, and a transcriptional signature of a senescence-associated secretory phenotype (SASP). SASP is a program that can be induced by oncogenes or DNA damage, and promotes growth arrest and tissue repair. The secretome of CD158d-stimulated senescent NK cells promoted vascular remodeling and angiogenesis as assessed by functional readouts of vascular permeability and endothelial cell tube formation. Retrospective analysis of the decidual NK cell transcriptome revealed a strong senescence signature. We propose that a positive function of senescence in healthy tissue is to favor reproduction through the sustained activation of NK cells to remodel maternal vasculature in early pregnancy.KIR2DL4 | microarray

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

“…Primary NK cells was stimulated with the ligand of KIR2DL4, sHLA-G upregulated p21 and, this was sensitive to inhibitors of DNA-PKcs. 53 These cells underwent changes characteristic of senescence, such as changes in cell shape and size, and staining for senescence-associated b-galactosidase. They also remained arrested at the G 0 /G 1 stage of the cell cycle and were refractory to apoptosis.…”

“…They also remained arrested at the G 0 /G 1 stage of the cell cycle and were refractory to apoptosis. 53 The induction of cellular senescence and the cell cycle arrest associated with it has been implicated in aging, cancer and tissue repair. 54 Although senescent cells do not divide or undergo apoptosis, they are metabolically very active and secrete an array of soluble mediators collectively termed the senescent-associated secretory phenotype (SASP).…”

Cellular senescence: from growth arrest to immunogenic conversion

“…In fact, immune cells may themselves undergo cellular senescence, a process that requires further investigations (Effros et al 2005;Rajagopalan et al 2012). As such, induction of cell senescence in immune cells may represent one aspect of immunosenescence, the gradual deterioration of the immune system, which consequently leads to impaired immunosurveillance of nonimmune senescent cells.…”

“…However, the length of time within the tissue is clearly a major factor in determining whether the effect of entry into senescence will be beneficial or deleterious to the organism. The appearance of senescent cells in the short-term probably facilitates important physiological functions such as tumour suppression (Braig et al 2005;Chen et al 2005;Michaloglou et al 2005;Collado et al 2005), wound healing (Krizhanovsky et al 2008;Jun et al 2010;Fitzner et al 2012;Kim et al 2013;Demaria et al 2014) and possibly placental development (Chuprin et al 2013;Rajagopalan and Long 2012;Zhang et al 2014). However, senescent cells are known to accumulate in vivo, possibly as a result of impaired immune clearance by an ageing immune system ).…”