Open AccessTrib1 regulates T cell differentiation during chronic infection by restraining the effector program
Author(s) -
Kelly S. Rome,
Sarah Stein,
Makoto Kurachi,
Jelena Petrović,
Gregory W. Schwartz,
Ethan A. Mack,
Sacha N. Uljon,
Wia Wu,
Anne G. DeHart,
Susan McClory,
Lanwei Xu,
Phyllis A. Gimotty,
Stephen C. Blacklow,
Robert B. Faryabi,
E. John Wherry,
Martha S. Jordan,
Warren S. Pear
Publication year - 2020
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20190888
Subject(s) - effector , biology , cytotoxic t cell , microbiology and biotechnology , t cell , t cell receptor , cd8 , regulator , il 2 receptor , immune system , immunology , genetics , gene , in vitro
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.