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 (TEX) impairs the ability of T cells to clear chronic infection or cancer. While TEX are hypofunctional, some TEX retain effector gene signatures, a feature that is associated with expression of KLRs (killer lectin-like receptors). Although KLR+ TEX 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 demonstrated that deleting the pseudokinase Trib1 shifted TEX towards CX3CR1+ intermediates (TINT) with robust enrichment of KLR+ TEX (TKLR) via clonal T cell expansion. Adoptive transfer studies demonstrate this shift towards a CD8+ TKLR in Trib1 deficient cells is CD8-intrinsic, while CD4-depletion studies demonstrate that CD4+ T cells are required for optimal viral control in Trib1 conditional knockout mice. Further, Trib1 loss augmented anti-PD-L1 blockade to improve viral clearance. These data identify Trib1 as an important regulator of CD8+ TEX whose targeting enhances the TKLR effector state and improves checkpoint inhibitor therapy. Overall design: Activated (CD44+) T cells (TCRb+) were sorted from the spleens of either CD4-Cre Trib1 +/+ or F/F mice at day 15 post-infection with LCMV cl13. Cells were then subjected to single cell TCR-sequencing on the droplet based 10X genomics platform