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

The Journal of Experimental Medicine
Kelly S RomeWarren S Pear

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.

References

Jan 21, 1997·Proceedings of the National Academy of Sciences of the United States of America·D E ZhangD G Tenen
Dec 22, 1998·The Journal of Experimental Medicine·A J ZajacR Ahmed
Apr 15, 2003·Nature Medicine·Joseph N BlattmanRafi Ahmed
Aug 10, 2004·The Journal of Biological Chemistry·Endre Kiss-TothSteven K Dower
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Jun 24, 2006·Science·Ling QiMarc Montminy
Nov 14, 2006·Cancer Cell·Karen KeeshanWarren S Pear
Jun 20, 2007·The Journal of Biological Chemistry·Takahiro NaikiAtsushi Miyajima
Oct 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Kenichiro ShimataniNagahiro Minato
Jul 9, 2010·Blood·Takashi YokoyamaTakuro Nakamura
Aug 6, 2010·Cold Spring Harbor Perspectives in Biology·Margot ThomeStephan Hailfinger
Dec 14, 2011·Proceedings of the National Academy of Sciences of the United States of America·Rachael D AubertRafi Ahmed
Jan 24, 2012·Nature Reviews. Immunology·Susan L SwainTara M Strutt
Mar 12, 2013·Trends in Immunology·Suman Paul, Brian C Schaefer
May 17, 2013·The Journal of Clinical Investigation·Erin E WestRafi Ahmed
Jul 19, 2013·Biochemical Society Transactions·Fiona Lohan, Karen Keeshan
Aug 21, 2013·Immunological Reviews·Tamara Veiga-PargaBarry T Rouse
Aug 13, 2014·The Journal of Experimental Medicine·Pablo Penaloza-MacMasterRafi Ahmed
Nov 16, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Shinya TanakaChen Dong
Mar 24, 2015·Trends in Immunology·Kristen E Pauken, E John Wherry
May 3, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·Hyo Jin ParkSang-Jun Ha
Jul 25, 2015·Nature Reviews. Immunology·E John Wherry, Makoto Kurachi
Sep 9, 2015·The Journal of Clinical Investigation·Robert C BauerDaniel J Rader
Apr 5, 2016·Structure·Sacha UljonStephen C Blacklow
May 19, 2016·PloS One·Sarah J SteinWarren S Pear
Jul 16, 2016·Biological Chemistry·Isabel Meininger, Daniel Krappmann

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Citations

Apr 23, 2021·Current Opinion in Lipidology·Krista Y Hu, Robert C Bauer
Jul 3, 2021·Cancers·Hamish D McMillanPeter D Mace

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Methods Mentioned

BETA
flow cytometry
PMA
ELISA
scRNA-seq
pull-down
immunoprecipitation
coimmunoprecipitation
PCR
FACS
Transfection

Software Mentioned

GEO2R
Broad GSEA
Cell Ranger
FlowJo
GraphPad Prism
Gene Set Enrichment Analysis ( GSEA )
TooManyCells
pandas
GSEA
TreeStar

Related Concepts