Signaling via IL-2 and IL-4 in JAK3-deficient severe combined immunodeficiency lymphocytes: JAK3-dependent and independent pathways.
Both IL-2 and IL-4 bind to receptors containing the common gamma chain and JAK3. Although JAK3 is required for proper lymphoid development, the precise roles of this kinase in IL-2 and IL-4 signaling in lymphocytes have not been defined. Here, we have studied IL-2 and IL-4 signaling in B cell lines lacking JAK3. Although IL-2-induced phosphorylation of IL-2R beta, JAK1, and STAT5 all required the presence of JAK3, IL-4-mediated phosphorylation of JAK1, STAT6, and insulin receptor substrates 1 and 2 did not. However, IL-4-induced effects were clearly improved following JAK3 expression. These data indicate that IL-4 signaling occurs in the absence of of JAK3, but is comparatively inefficient. These findings may help in understanding the pathogenesis of the immunodeficiency that occurs with mutations of JAK3 and may suggest a mechanism for the pleiotropic effects of IL-4.
Oakes
S A
SA
Howard Hughes Medical Institute, National Institutes of Health, Research Scholars Program, Bethesda, Maryland 20892, USA.
Candotti
F
F
Johnston
J A
JA
Chen
Y Q
YQ
Ryan
J J
JJ
Taylor
N
N
Liu
X
X
Hennighausen
L
L
Notarangelo
L D
LD
Paul
W E
WE
Blaese
R M
RM
O'Shea
J J
JJ
D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007376:Interleukin-2 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D008894:Milk Proteins; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017455:Receptors, IgE / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; D016511:Severe Combined Immunodeficiency / Q000209:etiology / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D008894:Milk Proteins; D010750:Phosphoproteins; D017455:Receptors, IgE; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053616:Janus Kinase 3