Trib1 controls antiviral immunity by restraining CD4 and CD8 T cell effector responses during chronic infection

Abstract

Abstract During chronic infection, the magnitude of the antiviral T cell response is determined by the balance between T cell effector (TEFF) function and T cell exhaustion. While CD8 T cell exhaustion has been extensively characterized, how TEFF responses are regulated during chronic antigen exposure is less clear. We identify Tribbles Pseudokinase 1 (Trib1) as a central regulator of the TEFF response to chronic infection. We show that Trib1 expression is elevated in activated T cells and in human or mouse T cells following chronic infection. In chronically infected mice, T cell-specific deletion of Trib1 enhanced CD4 and CD8 TEFF expansion, persistence and function and reduced viral load. Mechanistically, we show that Trib1 functions as a negative regulator of signaling downstream of the T cell receptor (TCR), whereby Trib1 expression disrupts TCR signaling complexes. These data support a model of negative feedback regulation whereby Trib1 restrains TCR signaling and downstream function. Together, our work shows that Trib1 functions to restrain the magnitude and duration of the TEFF response, at least in part through the disruption of TCR signaling complexes, and reveals a new regulatory node downstream of TCR signaling that is critical during chronic infection. In light of growing interest in checkpoint blockade therapies that act to overcome exhaustion during chronic antigen exposure, our work reveals an important new avenue for enhancing the efficacy of current T cell reactivation strategies during chronic disease.