Dichotomous regulation of progenitor-like CD8 T cells during chronic viral infection by TCF1 and type I interferon

Abstract

Abstract T cells develop into a dysfunctional state, called T-cell exhaustion, during chronic viral infections and cancer. However, how antigen-specific T cells persist in these situations is poorly understood. Here, we show that CD8 T cells differentiate into a less exhausted TCF1highTim3low subset and a more exhausted TCF1lowTim3high subset in chronic viral infection as well as human and mouse solid tumors. The TCF1highTim3low CD8 T cells, generated early after chronic lymphocytic choriomeningitis virus (LCMV) infection, persist better and mount a far stronger secondary response than TCF1lowTim3high cells. Importantly, TCF1highTim3low cells act as progenitor cells that are capable of both self-renewal and terminally differentiating into TCF1lowTim3high cells. We have further shown that cell-intrinsic TCF1 signaling is necessary and sufficient to program these progenitors early after infection. Cell-intrinsic TCF1 deficiency led to a progressive loss of anti-viral CD4 and CD8 T cell responses during the chronic phase of infection. Several pro-exhaustion factors, including Tim3, Cish, and Blimp1, are suppressed by TCF1. Conversely, TCF1 up-regulates Bcl6, which strongly enforces the progenitor fate. Moreover, cell-intrinsic type I interferon signal suppresses the differentiation of progenitor-like CD8 T cells, and antibody-mediated blockade of IFNAR1 enhances the differentiation of these CD8 T cells in a TCF1-dependent manner. Thus, our study not only identifies a CD8 progenitor population, which is critical for long-term persistence of anti-viral CD8 responses during chronic viral infection, but also uncovers both positive and negative regulators of the early programming of this population.