Epigallocatechin-3-gallate sensitizes IFN-γ-stimulated CD4+ T cells to apoptosis via alternative activation of STAT1

•EGCG selectively enhances IFN-γ-induced STAT1 activation in CD4+ T cells.•EGCG activates Src kinase in IFN-γ treated CD4+ T cells.•The enhancement of STAT1 activation by EGCG depends on Src activation and IFN-γR.•EGCG sensitizes IFN-γ treated CD4+ T cells to apoptosis.•EGCG alleviates CD4+ CD45RBhi CD25− T cell transfer induced chronic colitis.

Epigallocatechin-3-gallate (EGCG) exerts anti-inflammatory properties on immune cells and binds to CD4 molecules. However, the effects of EGCG on CD4+ T cells remain largely unknown. Here, we found that EGCG enhanced IFN-γ-induced signal transducer and activator of transcription 1 (STAT1) activation in primary CD4+ T cells from C57BL/6 mice and in a human leukemic CD4+ T-cell line of Hut 78 cells, while it inhibited the classical pathway of IFN-γ signaling including activating phosphorylations of Janus kinase (JAK) 1, JAK2 and STAT3, forming interferon-γ activated sequence (GAS)-binding STAT1 homodimers, and producing pro-inflammatory chemokine (C-X-C motif) ligand 9 (CXCL9). CD4 blockade did not suppress the increase in IFN-γ-induced STAT1 activation in CD4+ T cells by EGCG. Furthermore, activation of Src kinase was also triggered by IFN-γ plus EGCG in both Hut 78 and primary CD4+ T cells. Interestingly, EGCG promoted apoptosis of CD4+ T cells treated with IFN-γ. The increases in STAT1 activation and apoptosis induced by EGCG in IFN-γ-activated CD4+ T cells were almost completely abolished by a selective Src family kinase inhibitor, SU6656. Moreover, EGCG alleviates CD4+ CD45RBhi CD25− T cell transfer induced colitis with less accumulation of CD4+ T cells in the colon. In conclusion, the present study reports an alternative activation of STAT1 via Src by EGCG in IFN-γ-activated CD4+ T cells, which promotes the apoptosis of IFN-γ-activated CD4+ T cells and contributes to the improvement of T cell-mediated colitis. Our findings suggest a novel role of EGCG in regulating IFN-γ signaling and controlling inflammation.