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

T cell exhaustion (T(EX)) impairs the ability of T cells to clear chronic infection or cancer. While exhausted T cells are hypofunctional, some exhausted T cells retain effector gene signatures, a feature that is associated with expression of KLRs (killer lectin-like receptors). Although KLR(+) T cells may improve control of chronic antigen, the signaling molecules regulating this population are poorly understood. Using scRNA-seq, flow cytometry, RNA velocity, and scTCR-seq, we demonstrate that deleting the pseudokinase Trib1 shifts T(EX) towards CX3CR1(+) intermediates (T(INT)) with robust enrichment of KLR(+)CD8(+) T cells (T(KLR)) via clonal T cell expansion. These changes are associated with globally increased KLR gene expression throughout the exhaustion program. Further, Trib1 loss augments anti-PD-L1 blockade to improve viral clearance by expanding the T(KLR) population. Together, these data identify Trib1 as an important regulator of T cell exhaustion whose targeting enhances the KLR(+) effector state and improves the response to checkpoint inhibitor therapy.