The pseudokinase Trib1 regulates the transition of exhausted T cells to a KLR CD8 effector state, and its deletion improves checkpoint blockade.

CD8 T cell exhaustion (T) impairs the ability of T cells to clear chronic infection or cancer. While T are hypofunctional, some T retain effector gene signatures, a feature associated with killer lectin-like receptor (KLR) expression. Although KLR T (T) may improve control of chronic antigen, the signaling molecules regulating this population are poorly understood. Using single-cell RNA sequencing (scRNA-seq), flow cytometry, RNA velocity, and single-cell T cell receptor sequencing (scTCR-seq), we demonstrate that deleting the pseudokinase Trib1 shifts T toward CX3CR1 intermediates with robust enrichment of T via clonal T cell expansion. Adoptive transfer studies demonstrate this shift toward CD8 T in Trib1-deficient cells is CD8 intrinsic, while CD4-depletion studies demonstrate CD4 T cells are required for improved viral control in Trib1 conditional knockout mice. Further, Trib1 loss augments anti-programmed death-ligand 1 (PD-L1) blockade to improve viral clearance. These data identify Trib1 as an important regulator of CD8 T whose targeting enhances the T effector state and improves checkpoint inhibitor therapy.