Trib1 regulates T cell differentiation during chronic infection by restraining the effector program
Open Access
- 9 March 2020
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 217 (5)
- https://doi.org/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.Funding Information
- National Institutes of Health (P30CA016520)
- National Institutes of Health (R01AI047833, R35CA220340, F31CA189661, T32CA009140, T32HL743937, F30HL136127, K08CA166227, P30CA016520, T32CA009615)
- National Science Foundation (DGE-1321851)
- Patel Family Scholars Award
- American Cancer Society (PF-15-065-01-TBG)
- Samuel Waxman Cancer Research Foundation
- Alex’s Lemonade Stand Foundation for Childhood Cancer
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