Complementary roles for CD19 and Bruton's tyrosine kinase in B lymphocyte signal transduction

Manabu Fujimoto, Jonathan C. Poe, Anne B. Satterthwaite, Matthew I. Wahl, Owen N. Witte, Thomas F. Tedder

Research output: Contribution to journalArticle

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Abstract

CD19 and Bruton's tyrosine kinase (Btk) may function along common signaling pathways in regulating intrinsic and B cell Ag receptor (BCR)-induced signals. To identify physical and functional interactions between CD19 and Btk, a CD19-negative variant of the A20 B cell line was isolated, and CD19-deficient (CD19-1-) and CD19-overexpressing mice with the X-linked immunodeficient (Xid; Btk) mutation were generated. In A20 cells, Btk physically associated with CD19 following BCR engagement. CD19 and Btk interactions were not required for initial Btk phosphorylation, but CD19 expression maintained Btk in an activated state following BCR engagement. In primary B cells, CD19 signaling also required downstream Btk function since CD19-induced intracellular Ca2+ ([Ca2+]i) responses were modest in Xid B cells. In addition, CD19 overexpression did not normalize the Xid phenotype and most phenotypic and functional hallmarks of CD19 overexpression were not evident in these mice. However, CD19 and Btk also regulate independent signaling pathways since their combined loss had additive inhibitory effects on BCR-induced [Ca2+]i responses and CD19 deficiency induced a severe immunodeficiency in Xid mice. Thus, CD19 expression amplifies or prolongs Btk-mediated signaling, rather than serving as a required agent for Btk activation. Consistent with this, phosphatidyl-inositol 3-monophosphate kinase and Akt activation were normal in CD19-1- B cells following IgM engagement, although their kinetics of activation was altered. Thus, these biochemical and compound gene dosage studies indicate that Btk activation and [Ca2+]i responses following BCR engagement are regulated through multiple pathways, including a CD19/Src family kinase-dependent pathway that promotes the longevity of Btk signaling.

Original languageEnglish (US)
Pages (from-to)5465-5476
Number of pages12
JournalJournal of Immunology
Volume168
Issue number11
StatePublished - Jun 1 2002

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Signal Transduction
B-Lymphocytes
Agammaglobulinaemia tyrosine kinase
Gene Dosage
src-Family Kinases
Phosphatidylinositols
Immunoglobulin M
Phosphotransferases
Phosphorylation
Phenotype
Cell Line
Mutation

ASJC Scopus subject areas

  • Immunology

Cite this

Fujimoto, M., Poe, J. C., Satterthwaite, A. B., Wahl, M. I., Witte, O. N., & Tedder, T. F. (2002). Complementary roles for CD19 and Bruton's tyrosine kinase in B lymphocyte signal transduction. Journal of Immunology, 168(11), 5465-5476.

Complementary roles for CD19 and Bruton's tyrosine kinase in B lymphocyte signal transduction. / Fujimoto, Manabu; Poe, Jonathan C.; Satterthwaite, Anne B.; Wahl, Matthew I.; Witte, Owen N.; Tedder, Thomas F.

In: Journal of Immunology, Vol. 168, No. 11, 01.06.2002, p. 5465-5476.

Research output: Contribution to journalArticle

Fujimoto, M, Poe, JC, Satterthwaite, AB, Wahl, MI, Witte, ON & Tedder, TF 2002, 'Complementary roles for CD19 and Bruton's tyrosine kinase in B lymphocyte signal transduction', Journal of Immunology, vol. 168, no. 11, pp. 5465-5476.
Fujimoto, Manabu ; Poe, Jonathan C. ; Satterthwaite, Anne B. ; Wahl, Matthew I. ; Witte, Owen N. ; Tedder, Thomas F. / Complementary roles for CD19 and Bruton's tyrosine kinase in B lymphocyte signal transduction. In: Journal of Immunology. 2002 ; Vol. 168, No. 11. pp. 5465-5476.
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