The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness

著者: Tuoqi Wu, Yun Ji, E. Ashley Moseman, Haifeng C. Xu, Monica Manglani, Martha Kirby, Stacie M. Anderson, Robin Handon, Elizabeth Kenyon, Abdel G. Elkahloun, Weiwei Wu, Philipp A. Lang, Luca Gattinoni, Dorian B. McGavern, Pamela L. Schwartzberg - Science Immunology 2016 被引用: 646

cells. We show that TCF1 is both necessary and sufficient to support this progenitor-like CD8 subset, whereas cell-intrinsic type I interferon signaling suppresses their differentiation. Accordingly, cell-intrinsic TCF1 deficiency led to a loss of these progenitor CD8 T cells, sharp contraction of virus-specific T cells, and uncontrolled viremia. Mechanistically, TCF1 repressed several pro-exhaustion factors and induced Bcl6 in CD8 T cells, which promoted the progenitor fate. We propose that the TCF1-Bcl6 axis counteracts type I interferon to repress T cell exhaustion and maintain T cell stemness, which is critical for persistent antiviral CD8 T cell responses in chronic infection. These findings provide insight into the requirements for persistence of T cell immune responses in the face of exhaustion and suggest mechanisms by which effective T cell-mediated immunity may be enhanced during chronic infections and cancer.