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

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Science Immunology  09 Dec 2016:
Vol. 1, Issue 6, eaai8593
DOI: 10.1126/sciimmunol.aai8593

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TCF1 fine-tunes T cell exhaustion

Exhaustion of CD8+ T cells is observed in chronic viral infections and in the tumor microenvironment. Using chronic LCMV infection in mice, Wu et al. report that expression levels of the transcription factor T cell factor 1 (TCF1) determine the degree of T cell exhaustion. TCF1high CD8+ T cells are less exhausted as compared with TCF1low CD8+ T cells, and they play an essential role in controlling viremia in chronically infected mice. Blockade of type I interferon, a driver of T cell exhaustion, promoted expansion of TCF1high CD8+ Tcells. The studies have better defined the molecular features of exhausted T cells and suggest that targeting TCF1-driven pathways could be used to modulate T cell exhaustion.


During chronic viral infections and in cancer, T cells become dysfunctional, a state known as T cell exhaustion. Although it is well recognized that memory CD8 T cells account for the persistence of CD8 T cell immunity after acute infection, how exhausted T cells persist remains less clear. Using chronic infection with lymphocytic choriomeningitis virus clone 13 and tumor samples, we demonstrate that CD8 T cells differentiate into a less exhausted TCF1high and a more exhausted TCF1low population. Virus-specific TCF1high CD8 T cells, which resemble T follicular helper (TFH) cells, persist and recall better than do TCF1low cells and act as progenitor cells to replenish TCF1low 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.

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