Regulation of NKG2D+CD8+ T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism. (1st December 2016)

• Record Type: Journal Article
• Authors: Hu, Jiemiao; Batth, Izhar S.; Xia, Xueqing; Li, Shulin
• Is Part Of: Oncoimmunology. Volume 5:Number 12(2016)
• Publication Date: 2016-12-01
• Subjects: CD8+ T cells -- CD28 -- Lck -- NKG2D receptor -- pSTAT3; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2016.1252012
• Languages: English
• ISSNs: 2162-402X

Abstract

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 cells in vitro, as well as significantly improves the antitumor therapeutic effects in vivo in 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.