Engagement of TRAIL triggers degranulation and IFNγ production in human natural killer cells

Abstract

NK cells utilize a large array of receptors to screen their surroundings for aberrant or virus‐infected cells. Given the vast diversity of receptors expressed on NK cells we seek to identify receptors involved in the recognition of HIV‐1‐infected cells. By combining an unbiased large‐scale screening approach with a functional assay, we identify TRAIL to be associated with NK cell degranulation against HIV‐1‐infected target cells. Further investigating the underlying mechanisms, we demonstrate that TRAIL is able to elicit multiple effector functions in human NK cells independent of receptor‐mediated induction of apoptosis. Direct engagement of TRAIL not only results in degranulation but also IFNγ production. Moreover, TRAIL‐mediated NK cell activation is not limited to its cognate death receptors but also decoy receptor I, adding a new perspective to the perceived regulatory role of decoy receptors in TRAIL‐mediated cytotoxicity. Based on these findings, we propose that TRAIL not only contributes to the anti‐HIV‐1 activity of NK cells but also possesses a multifunctional role beyond receptor‐mediated induction of apoptosis, acting as a regulator for the induction of different effector functions.

Digital spatial profiling of human parathyroid tumors reveals cellular and molecular alterations linked to vitamin D deficiency

“…Notably, expression of GABBR1 ( gamma aminobutyric acid type B receptor 1 ), which our group has recently shown to oppose CaSR-mediated calcium sensing in the parathyroid ( 34 ), is significantly elevated in Def-Ts. Additional genes found to be significantly upregulated in these tumors act in signaling pathways controlling apoptosis (TNFSF10, tumor necrosis superfamily member 10 ) ( 35 , 36 ), cellular stress response (SGK1, serum glucocorticoid regulated kinase 1 ) ( 37 ), inositol-derived second messenger production (IPMK, inositol polyphosphate multikinase ) ( 38 ), and energetic metabolism (AMPD3, adenosine monophosphate deaminase 3 ) ( 39 ). Despite the higher preoperative PTH observed in vitamin D-deficient PHPT patients, PTH transcript abundance was not significantly different between tissue sources ( P = 0.2862 by one-way ANOVA) or when comparing chief to oxyphil cells ( P = 0.7284 by unpaired t -test).…”

iPSC‐derived NK cells with site‐specific integration of CAR19 and IL24 at the multi‐copy rDNA locus enhanced antitumor activity and proliferation

“…Recent studies have confirmed that NK cells may improve immunity via inducing degranulation via TRAIL. 52 Hence, it is reasonable that the changes we observed in CAR-iNK cells might contribute to NK-cell-mediated cytotoxicity.…”

Glucocorticoid receptor activation induces NK cells to produce AREG and restricts their anti-tumor activity in skin cancer

“…In cSCC (Figure 3C and Table S7), a relatively consistent trend for an upregulation of cluster unique genes that enhancing NK cell activation or expansion were detected in C0 (CD2, CD52) 61,62 , C1 (NCR3, OASL, NFKBIZ, TSC22D4) 63,64 , C2 (KLRC3, IKZF3, ETS1, NFIL3, JAK1, NKTR) 65,66 , and C4 (GNLY, TNFSF10) 67 , and a downregulation of immunosuppressive genes were concertedly detected in C0 (USP14) 68 , C1 (TNFRSF18, HLA-B, HLA-C) [69][70][71] , and C4 (IKZF2, LAG3, KIR2DL1) 30 , consistent with the elevated NK cell activation signatures in all NK cell clusters from the tumor of SCC. (Figure 2D).…”