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

Abstract

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.

Keywords: CD8 T cell exhaustion; CP: Immunology; Immune checkpoint blockade; LCMV clone 13; PD-L1; Tribbles; immnotherapy.