Activation of NK Cells by an Endocytosed Receptor for Soluble HLA-G

Abstract

Signaling from endosomes is emerging as a mechanism by which selected receptors provide sustained signals distinct from those generated at the plasma membrane. The activity of natural killer (NK) cells, which are important effectors of innate immunity and regulators of adaptive immunity, is controlled primarily by receptors that are at the cell surface. Here we show that cytokine secretion by resting human NK cells is induced by soluble, but not solid-phase, antibodies to the killer cell immunoglobulin-like receptor (KIR) 2DL4, a receptor for human leukocyte antigen (HLA)-G. KIR2DL4 was constitutively internalized into Rab5-positive compartments via a dynamin-dependent process. Soluble HLA-G was endocytosed into KIR2DL4–containing compartments in NK cells and in 293T cells transfected with KIR2DL4. Chemokine secretion induced by KIR2DL4 transfection into 293T cells occurred only with recombinant forms of KIR2DL4 that trafficked to endosomes. The profile of genes up-regulated by KIR2DL4 engagement on resting NK cells revealed a proinflammatory/proangiogenic response. Soluble HLA-G induced secretion of a similar set of cytokines and chemokines. This unique stimulation of resting NK cells by soluble HLA-G, which is endocytosed by KIR2DL4, implies that NK cells may provide useful functions at sites of HLA-G expression, such as promotion of vascularization in maternal decidua during early pregnancy.

KIR2DL5 alleles mark certain combination of activating KIR genes

“…It is interesting to note that KIR2DL4 that displays limited polymorphism, [27][28][29] and shares high structural homologies to KIR2DL5, binds to the conserved non-classical HLA-G molecule. 6,9 The known regulatory elements in the promoter region are conserved in all KIR2DL5 sequences. 13 Of the 21 distinct KIR2DL5 sequences, eight belong to 2DL5A and the remaining 13 belong to 2DL5B.…”

“…4 Despite clustering together into a discrete lineage with high structural homologies, the KIR2DL5 and 2DL4 differ substantially in their amino-acid sequences, genomic locations, population distributions, level of transcriptions, cellsurface expressions, ligand specificities and signaling functions. [5][6][7][8][9] The KIR2DL4 gene is present on most KIR haplotypes and occurs at a frequency of 100% in most populations, whereas KIR2DL5 is variable among KIR haplotypes and thus differs considerably between populations in its frequency. [10][11][12] Two copies of the KIR2DL5 genes have been characterized, KIR2DL5A and KIR2DL5B, that show 99.5-99.7% identity in their coding sequences.…”

“…14 KIR2DL5 displays a variegated distribution on the surface of CD56 dim NK cells, whereas the surface expression of KIR2DL4 appears to be restricted to the minority subset of KIR neg CD56 bright NK cells. 8,15 Although KIR2DL4 has been implicated in both inhibitory and activating functions, 6,[16][17][18] KIR2DL5 appears to be solely an inhibitory receptor. 7 Multiple sequences for both KIR2DL5A and KIR2DL5B loci have been characterized from individuals of different ethnic origins.…”

Anti-apoptotic seminal vesicle protein IV inhibits cell-mediated immunity

“…The blastocyst, however, is well equipped to counteract this harmful situation. Synthesis of HLA-G as a substitute of missing HLA class I, allows blastocysts not only to silence uNK and CTL anti-blastocyst cytotoxicity, but also to obtain uNK cooperation for embryo development by inducing these cells to secrete embryotrophic cytokines and factors promoting cell growth, angiogenesis, and EVT survival and invasiveness (Rouass-Freis et al, 1997;Moretta and Moretta, 2004;Perham, 2004;Rajagopalan et al, 2006). In addition, the occurrence in uterus at blastocyst implanting time of a high number of protective molecules (Leukemia Inhibitory Factor, heme oxygenase HO-1, IL-10, TGF-, etc.…”

Soluble HLA-G: Are they clinically relevant?

“…Rajagopalan et al [33] have recently showed that sHLA-G, following binding to the CD158d receptor on the surface of human resting NK cells, is endocytosed and triggers the expression of a set of chemokines and cytokines driving a proinflammatory/proangiogenic response. These findings suggest that NK cells can exert beneficial effects at sites of HLA-G expression, such as stimulation of vascularization in the maternal decidua during pregnancy.…”