CD7 drives CD8 T cell exhaustion during chronic viral infection

Viral or tumor persistence is often associated with CD8 T cell "exhaustion," a differentiation process characterized by co-inhibitory receptor upregulation and loss of effector function. Recent data show that "exhausted" T cells are a heterogenous population that includes a progenitor subset that transitions through an intermediate state before bifurcating into either terminally exhausted cells or cytolytic effector cells crucial for viral or tumor control. However, the mechanisms underlying this bifurcation process remains unclear. In this study, we show that the Ig superfamily member CD7 is selectively upregulated on terminally exhausted T cells responding to chronic viral infection and cancer. Genetic deletion of CD7 in virus-specific CD8 T cells resulted in an expansion of effector T cells and reduced exhausted T cell formation, decreased inhibitory receptor expression, and augmented IFN-γ secretion following chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. Deletion of CD7 in antigen-specific CD8 T cells conferred enhanced control over viral replication during chronic LCMV infection and suppressed tumor outgrowth in a preclinical lung cancer model. Conversely, retroviral overexpression of CD7 was sufficient to drive T cell exhaustion and upregulate expression of immune checkpoint inhibitory receptors and the transcription factor Tox. Mechanistically, our data indicate that CD7 may function to amplify TCR signaling strength and the induction of TCR-sensitive transcription factors such as Nur77 and Tox that program T cell exhaustion. These data highlight CD7 as a potential therapeutic target that can be manipulated to improve effector CD8 T cell-mediated control over chronic infection and/or malignancy.