Interleukin-4 signaling in B lymphocytes from patients with X-linked severe combined immunodeficiency.
Interleukin-4 (IL-4) is an important cytokine for B and T lymphocyte function and mediates its effects via a receptor that contains gammac. B cells derived from patients with X-linked severe combined immunodeficiency (X-SCID) are deficient in gammac and provide a useful model in which to dissect the role of this subunit in IL-4-mediated signaling. We found that although IL-4 stimulation of X-SCID B cells did not result in Janus tyrosine kinase-3 (JAK3) phosphorylation, other IL-4 substrates including JAK1 and IRS-1 were phosphorylated. Additionally, we detected signal transducers and activators of transcription 6 (STAT6) tyrosine phosphorylation and DNA binding activity in X-SCID B cells with a wide range of gammac mutations. However, reconstitution of these X-SCID B cells with gammac enhanced IL-4-mediated responses including STAT6 phosphorylation and DNA binding activity and resulted in increased CD23 expression. Thus, gammac is not necessary to trigger IL-4-mediated responses in B cells, but its presence is important for optimal IL-4-signaling. These results suggest that two distinct IL-4 signaling pathways exist.
Taylor
N
N
Division of Research Immunology and Bone Marrow Transplantation, Childrens Hospital Los Angeles, Los Angeles, California 90027, USA. taylor@igm.cnrs-mop.fr
Candotti
F
F
Smith
S
S
Oakes
S A
SA
Jahn
T
T
Isakov
J
J
Puck
J M
JM
O'Shea
J J
JJ
Weinberg
K
K
Johnston
J A
JA
D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D050800:STAT6 Transcription Factor; D016511:Severe Combined Immunodeficiency / Q000276:immunology*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4