TGF-β inhibits central memory cell differentiation in CD8 T-cells (52.14)

Abstract

Abstract Generation of a robust long-term T-cell memory would be expected to fortify vaccines and enhance host protection against infectious diseases and cancer immunotherapy. TGF-β is a well-known immune suppressive cytokine and in initial studies its ability to interfere with the generation of CD8+ central memory (CM) T-cells was confirmed. Exogenous TGF-β addition to isolated splenocytes from C57BL/6 or T-cells from F5 transgenic mice inhibited the differentiation of CD44+/CD62L+ CM T-cells in a dose-dependent manner. The addition of 0.5 ng/ml of TGF-β reduced the number of CD44+/CD62L+ CM by 50%, independent of any changes in CD8+ T-cell proliferation or apoptosis. Inhibition CM T-cell generation by TGF-β was reversed with the addition of SD208, a TGF-β RI kinase inhibitor. Signal transduction studies revealed that TGF-β selectively activates SMAD2, not SMAD independent pathways such as p38 MAPK in CD8+ T cells. SD208 interfered with SMAD2 activation and reversed the TGF-β-mediated suppression of CM T-cells. Interestingly, the TGF-β RI kinase inhibitor also suppressed S6, a down-stream mTORC1substrate. This study suggests that inhibiting TGF-β with the addition of TGF-β RI kinase inhibitor facilitates the generation of a more robust CM T-cell response, suggesting that combining TGF-β inhibition with vaccination could generate long-lasting CD8+ central memory immunity.