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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 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.

SUBMITTER: Hu J

PROVIDER: S-EPMC5214668 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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

Hu Jiemiao J Batth Izhar S IS Xia Xueqing X Li Shulin S

Oncoimmunology 20161101 12

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 ...[more]

PMID: 28123894

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Project description:Background: A keloid is a benign skin tumor that extends beyond the initial injury area, and its pathologic mechanism remains unclear. Method: High-throughput sequencing data were obtained from normal skin tissue of patients with keloids (Group N) and healthy controls (Group C). Important genes were mined by bioinformatics analysis and identified by RT-qPCR, Western blotting, immunohistochemistry and immunofluorescence assays. The CIBERSORT algorithm was used to convert gene expression information into immune cell information. Flow cytometry was used to verify the key immune cells. Fluorescence-activated cell sorting coculture and CCK8 experiments were used to explore the effect of CD8+ T cells on keloid-associated fibroblasts. Neural network models were used to construct associations among CD28, CD8+ T cells and the severity of keloids and to identify high-risk values. Result: The expression levels of costimulatory molecules (CD28, CD80, CD86 and CD40L) in the skin tissue of patients with keloids were higher than the levels in healthy people (p < 0.05). The number of CD8+ T cells was significantly higher in Group N than in Group C (p < 0.05). The fluorescence intensities of CD28 and CD8+ T cells in Group N were significantly higher than those in Group C (p = 0.0051). The number and viability of fibroblasts cocultured with CD8+ T cells were significantly reduced compared with those of the control (p < 0.05). The expression of CD28 and CD8+ T cells as the input layer may be predictors of the severity of keloids with mVSS as the output layer. The high-risk early warning indicator for CD28 is 10-34, and the high-risk predictive indicator for CD8+ T cells is 13-28. Conclusions: The abnormal expression of costimulatory molecules may lead to the abnormal activation of CD8+ T cells. CD8+ T cells may drive keloid-associated immunosuppression. The expression of CD28 and CD8+ T cells as an input layer may be a predictor of keloid severity. CD28 and CD8+ T cells play an important role in the development of keloids.

Dataset Information

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

Publications

Regulation of NKG2D<sup>+</sup>CD8<sup>+</sup> T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism.

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