An essential role for Bruton's [corrected] tyrosine kinase in the regulation of B-cell apoptosis.
Mutations of the Bruton's tyrosine kinase (btk) gene cause X-linked agammaglobulinemia (XLA) in humans and X-linked immune deficiency (Xid) in mice. To establish the BTK role in B-cell activation we examined the responses of wild-type and Xid B cells to stimulation through surface IgM and CD40, the transducers of thymus independent-type 2 and thymus-dependent activation, respectively. Wild-type BTK was necessary for proliferation induced by soluble anti-IgM (a prototype for thymus independent-type 2 antigen), but not for responses to soluble CD40 ligand (CD40L, the B-cell activating ligand expressed on T-helper cells). In the absence of wild-type BTK, B cells underwent apoptotic death after stimulation with anti-IgM. In the presence of wild-type but not mutated BTK, anti-IgM stimulation reduced apoptotic cell death. In contrast, CD40L increased viability of both wild-type and Xid B cells. Importantly, viability after stimulation correlated with the induced expression of bcl-XL. In fresh ex vivo small resting B cells from wild-type mice there was only barely detectable bcl-XL protein, but there was more in the larger, low-density ("activated") splenic B cells and peritoneal B cells. In vitro Bcl-XL induction following ligation of sIgM-required BTK, was cyclosporin A (CsA)-sensitive and dependent on extracellular Ca2+. CD40-mediated induction of bcl-x required neither wild-type BTK nor extracellular Ca2+ and was insensitive to CsA. These results indicate that BTK lies upstream of bcl-XL in the sIgM but not the CD40 activation pathway. bcl-XL is the first induced protein to be placed downstream of BTK.
Anderson
J S
JS
Department of Pathology, Tufts University School of Medicine, Boston, MA, USA.
Teutsch
M
M
Dong
Z
Z
Wortis
H H
HH
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology* / Q000201:enzymology; D023201:CD40 Ligand; D002470:Cell Survival; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology*; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008808:Mice, Inbred CBA; D011090:Polyenes / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D020123:Sirolimus; D013601:T-Lymphocytes / Q000276:immunology; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D008562:Membrane Glycoproteins; D011090:Polyenes; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D051020:bcl-X Protein; D023201:CD40 Ligand; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D020123:Sirolimus