title: Regulation of NKG2D+CD8+T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism.
abstract: The natural killer (NK) group 2D (NKG2D) receptor, which displays on mouse and human NK cells, activates CD8+T cells and small subsets of other T cells. NKG2D+CD8+T cells play critical roles in both innate and adaptive immunity upon engagement with NKG2D ligands to eliminate tumor and infected cells. Despite the important role of NKG2D+CD8+T cells in immune surveillance, the mechanisms of how NKG2D expression on CD8+T cells is regulated remain poorly defined. We treated mouse and human CD8+T cells with CD80 recombinant protein, plus a pharmacologic model with small molecular inhibitors to determine which signaling pathway leads to NKG2D regulation on CD8+T cells. This study revealed that CD28 activation gives rise to sustained NKG2D expression on both mouse and human CD8+T cells in a signal transducer and activator of transcription 3 (STAT3) phosphorylation-dependent manner. Further, we found that CD28 activation stimulated sustained activation of the tyrosine kinase Lck, which recruits and triggers Janus kinase/STAT3 signaling to phosphorylate STAT3, and in turn increases NKG2D expression. Moreover, NKG2D induction on CD8+T cells exerts cytolytic activity against target tumor cellsin vitro, as well as significantly improves the antitumor therapeutic effectsin vivoin an NKG2D-dependent manner. Taken together, these results elucidated a novel mechanism of NKG2D regulation by phosphorylated STAT3 (pSTAT3) on CD8+T cells upon CD28 activation. This mechanism may shed light on the effectiveness of CD80-based, NKG2D-dependent antitumor immunotherapy.
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Jiemiao
authors.initials: J
authors.lastname: Hu
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Izhar S
authors.initials: IS
authors.lastname: Batth
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Xia
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Shulin
authors.initials: S
authors.lastname: Li
keywords: CD28; CD8+ T cells; Lck; NKG2D receptor; pSTAT3