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.
Competing Interests: Declaration of interests E.J.W. is a member of PICI and advisor for Danger Bio, Marengo, Janssen, New Limit, Pluto Immunotherapeutics, Related Sciences, Rubius Therapeutics, Synthekine, and Surface Oncology. E.J.W. is a founder of Surface Oncology, Danger Bio, and Arsenal Biosciences.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)