Bruton's tyrosine kinase is not essential for B cell survival beyond early developmental stages

Lindsay E. Nyhoff, Emily S. Clark, Bridgette L. Barron, Rachel H. Bonami, Wasif Khan, Peggy L. Kendall

Research output: Contribution to journalArticle

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Abstract

Bruton's tyrosine kinase (Btk) is a crucial regulator of B cell signaling and is a therapeutic target for lymphoma and autoimmune disease. BTK-deficient patients suffer from humoral immunodeficiency, as their B cells fail to progress beyond the bone marrow. However, the role of Btk in fully developed, mature peripheral B cells is not well understood. Analysis using BTK inhibitors is complicated by suboptimal inhibition, off-target effects, or failure to eliminate BTK's adaptor function. Therefore a Btkflox/Cre-ERT2 mouse model was developed and used to excise Btk after B cell populations were established. Mice lacking Btk from birth are known to have reduced follicular (FO) compartments, with expanded transitional populations, suggesting a block in development. In adult Btkflox/Cre-ERT2 mice, Btk excision did not reduce FO B cells, which persisted for weeks. Autoimmune-prone B1 cells also survived conditional Btk excision, contrasting their near absence in global Btk-deficient mice. Therefore, Btk supports BCR signaling during selection into the FO and B1 compartments, but is not needed to maintain these cell populations. B1-related natural IgM levels remained normal, contrasting global Btk deficiency, but B cell proliferation and T-independent type II immunization responses were blunted. Thus, B cells have nuanced signaling responses that are differentially regulated by Btk for development, survival, and function. These findings raise the possibility that Btk may also be expendable for survival of mature human B cells, therefore requiring prolonged dosing to be effective, and that success of BTK inhibitors may depend in part on off-target effects.

Original languageEnglish (US)
Pages (from-to)2352-2361
Number of pages10
JournalJournal of Immunology
Volume200
Issue number7
DOIs
StatePublished - Apr 1 2018

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Cell Survival
B-Lymphocytes
Agammaglobulinaemia tyrosine kinase
Population
Autoimmune Diseases
Immunoglobulin M
Immunization
Lymphoma
Bone Marrow
Cell Proliferation
Parturition
Survival

ASJC Scopus subject areas

  • Immunology

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Bruton's tyrosine kinase is not essential for B cell survival beyond early developmental stages. / Nyhoff, Lindsay E.; Clark, Emily S.; Barron, Bridgette L.; Bonami, Rachel H.; Khan, Wasif; Kendall, Peggy L.

In: Journal of Immunology, Vol. 200, No. 7, 01.04.2018, p. 2352-2361.

Research output: Contribution to journalArticle

Nyhoff, Lindsay E. ; Clark, Emily S. ; Barron, Bridgette L. ; Bonami, Rachel H. ; Khan, Wasif ; Kendall, Peggy L. / Bruton's tyrosine kinase is not essential for B cell survival beyond early developmental stages. In: Journal of Immunology. 2018 ; Vol. 200, No. 7. pp. 2352-2361.
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