Jak3 deficiency blocks innate lymphoid cell development

Mucosal Immunology
M L RobinetteMarco Colonna

Abstract

Loss-of-function mutations in the tyrosine kinase JAK3 cause autosomal recessive severe combined immunodeficiency (SCID). Defects in this form of SCID are restricted to the immune system, which led to the development of immunosuppressive JAK inhibitors. We find that the B6.Cg-Nr1d1tm1Ven/LazJ mouse line purchased from Jackson Laboratories harbors a spontaneous mutation in Jak3, generating a SCID phenotype and an inability to generate antigen-independent professional cytokine-producing innate lymphoid cells (ILCs). Mechanistically, Jak3 deficiency blocks ILC differentiation in the bone marrow at the ILC precursor and the pre-NK cell progenitor. We further demonstrate that the pan-JAK inhibitor tofacitinib and the specific JAK3 inhibitor PF-06651600 impair the ability of human intraepithelial ILC1 (iILC1) to produce IFN-γ, without affecting ILC3 production of IL-22. Both inhibitors impaired the proliferation of iILC1 and ILC3 and differentiation of human ILC in vitro. Tofacitinib is currently approved for the treatment of moderate-to-severely active rheumatoid arthritis. Both tofacitinib and PF-06651600 are currently in clinical trials for several other immune-mediated conditions. Our data suggest that therapeutic inhibition of J...Continue Reading

References

Nov 3, 1995·Science·T NosakaJ N Ihle
Jan 6, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·S Gozalo-SanmillanL J Berg
Jan 22, 2005·Immunological Reviews·Marko PesuJohn J O'Shea
Jun 11, 2010·Proceedings of the National Academy of Sciences of the United States of America·Marina CellaMarco Colonna
Aug 17, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Stéphane ChappazDaniela Finke
Mar 9, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·Kamran GhoreschiJohn J O'Shea
Apr 24, 2012·Immunity·Jean-Laurent CasanovaLuigi D Notarangelo
Aug 10, 2012·The New England Journal of Medicine·Roy FleischmannUNKNOWN ORAL Solo Investigators
Aug 17, 2012·The New England Journal of Medicine·William J SandbornUNKNOWN Study A3921063 Investigators
Sep 24, 2013·Trends in Immunology·Jianhua YuMichael A Caligiuri
Jan 15, 2014·Journal of Medicinal Chemistry·James D ClarkJean-Baptiste Telliez
Feb 11, 2014·Nature·Michael G ConstantinidesAlbert Bendelac
Jul 31, 2014·The New England Journal of Medicine·Sung-Yun PaiRichard J O'Reilly
Sep 23, 2014·Immunity·Andrew N J McKenzieGerard Eberl
Jan 27, 2015·Nature Immunology·Michelle L RobinetteUNKNOWN Immunological Genome Consortium
Apr 4, 2015·Proceedings of the National Academy of Sciences of the United States of America·Michael G ConstantinidesAlbert Bendelac
May 23, 2015·Science·Gérard EberlAndrew N J McKenzie
Jun 13, 2015·Nature Reviews. Immunology·Nicolas SerafiniJames P Di Santo
Jun 30, 2015·Nature Medicine·Gregory F Sonnenberg, David Artis
Aug 19, 2015·Nature Immunology·Qi YangAvinash Bhandoola
Oct 17, 2015·Immunology Letters·C P PetersH Spits
Dec 29, 2015·Current Opinion in Immunology·Kerstin Juelke, Chiara Romagnani
Feb 16, 2016·Nature Immunology·Åsa K BjörklundJenny Mjösberg
Jun 22, 2016·Nature Immunology·Sascha CordingGérard Eberl
Jun 22, 2016·Nature Immunology·Christoph S N Klose, David Artis
Jun 22, 2016·Nature Immunology·Erin C Zook, Barbara L Kee
Oct 21, 2016·Nature Immunology·Frédéric VélyEric Vivier
Nov 8, 2016·The Journal of Allergy and Clinical Immunology·Michelle L Robinette, Marco Colonna
Apr 1, 2017·Nature Communications·Michelle L RobinetteMarco Colonna

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Citations

Feb 27, 2019·Rheumatology·Massimo GadinaJohn J O'Shea
Feb 6, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Natalija SimonovićBirgit Strobl
Jul 16, 2020·Experimental Biology and Medicine·Longfei PanHongyan Tian
Oct 9, 2018·Immunological Reviews·Helena StabileGiuseppe Sciumè
Jan 11, 2020·Frontiers in Immunology·Abdalla Sheikh, Ninan Abraham
Jul 28, 2019·Nature Reviews. Immunology·Gregory F Sonnenberg, Matthew R Hepworth
Apr 8, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Massimo GadinaJohn J O'Shea
Jan 11, 2020·Frontiers in Immunology·Laura VianMassimo Gadina
Nov 5, 2019·Frontiers in Immunology·Gianluca ScarnoGiuseppe Sciumè
Nov 1, 2017·Frontiers in Immunology·David R Withers, Matthew R Hepworth
Jul 13, 2018·Journal of Leukocyte Biology·Massimo GadinaJohn J O'Shea
Dec 19, 2018·Frontiers in Oncology·Juuli RaivolaOlli Silvennoinen
Nov 30, 2019·Frontiers in Immunology·Dagmar GotthardtEva Maria Putz
Oct 1, 2020·Clinical and Translational Medicine·Julie HablotDavid Moulin
Jan 24, 2019·Frontiers in Immunology·Agnieszka Witalisz-SieprackaVeronika Sexl
Apr 6, 2021·Frontiers in Immunology·Xiang Wang, Xiang-Yu Zhao
May 28, 2019·Cytokine & Growth Factor Reviews·Nicolas SaillietSophie Brouard
May 10, 2021·The Journal of Allergy and Clinical Immunology·Maryam Ghaedi, Fumio Takei
Jun 1, 2021·Frontiers in Cell and Developmental Biology·Eirini Sofia Fasouli, Eleni Katsantoni
Jun 15, 2021·Frontiers in Pharmacology·Shahin ShamsJudith F Ashouri

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Methods Mentioned

BETA
exome sequencing
FACS
PCR

Software Mentioned

GraphPad
Burrows
Prism
HaplotypeCaller
Wheeler Aligner ( BWA ) Analysis Toolkit
FlowJo
Treestar

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