The pseudokinase Trib1 regulates the transition of exhausted T cells to a KLR+ CD8+ effector state, and its deletion improves checkpoint blockade
Susan E. McClory,
Oishi Bardhan,
Kelly S. Rome,
Josephine R. Giles,
Amy E. Baxter,
Lanwei Xu,
Phyllis A. Gimotty,
Robert B. Faryabi,
E. John Wherry,
Warren S. Pear,
Martha S. Jordan
Affiliations
Susan E. McClory
Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Oishi Bardhan
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Kelly S. Rome
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Josephine R. Giles
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Amy E. Baxter
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Lanwei Xu
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Phyllis A. Gimotty
Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Robert B. Faryabi
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
E. John Wherry
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Warren S. Pear
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
Martha S. Jordan
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
Summary: 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 associated with killer lectin-like receptor (KLR) expression. Although KLR+ TEX (TKLR) 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 TEX toward CX3CR1+ intermediates with robust enrichment of TKLR via clonal T cell expansion. Adoptive transfer studies demonstrate this shift toward CD8+ TKLR 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+ TEX whose targeting enhances the TKLR effector state and improves checkpoint inhibitor therapy.
