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(EX)) impairs the ability of T cells to clear chronic infection or cancer. While T(EX) are hypofunctional, some T(EX) retain effector gene signatures, a feature associated with killer lectin-like receptor (KLR) expression. Although KLR(+) T(EX) (T(KLR)) 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(EX) toward CX3CR1(+) intermediates with robust enrichment of T(KLR) via clonal T cell expansion. Adoptive transfer studies demonstrate this shift toward CD8(+) T(KLR) 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(EX) whose targeting enhances the T(KLR) effector state and improves checkpoint inhibitor therapy.