Trib1 regulates T cell differentiation during chronic infection by restraining the effector program

J Exp Med. 2020 May 4;217(5):e20190888. doi: 10.1084/jem.20190888.

Abstract

In chronic infections, the immune response fails to control virus, leading to persistent antigen stimulation and the progressive development of T cell exhaustion. T cell effector differentiation is poorly understood in the context of exhaustion, but targeting effector programs may provide new strategies for reinvigorating T cell function. We identified Tribbles pseudokinase 1 (Trib1) as a central regulator of antiviral T cell immunity, where loss of Trib1 led to a sustained enrichment of effector-like KLRG1+ T cells, enhanced function, and improved viral control. Single-cell profiling revealed that Trib1 restrains a population of KLRG1+ effector CD8 T cells that is transcriptionally distinct from exhausted cells. Mechanistically, we identified an interaction between Trib1 and the T cell receptor (TCR) signaling activator, MALT1, which disrupted MALT1 signaling complexes. These data identify Trib1 as a negative regulator of TCR signaling and downstream function, and reveal a link between Trib1 and effector versus exhausted T cell differentiation that can be targeted to improve antiviral immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Differentiation*
  • Cell Line
  • Chronic Disease
  • Humans
  • Immunity
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lymphocyte Activation / immunology
  • Lymphocyte Subsets / immunology
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic Choriomeningitis / virology*
  • Lymphocytic choriomeningitis virus / immunology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / metabolism
  • Phenotype
  • Protein Binding
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / metabolism
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • Transcription, Genetic
  • Viral Load

Substances

  • Intracellular Signaling Peptides and Proteins
  • Trib1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Malt1 protein, mouse
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein