A CD19-dependent signaling pathway regulates autoimmunity in Lyn-deficient mice.
CD19 and the Src family protein tyrosine kinases (PTKs) are important regulators of intrinsic signaling thresholds in B cells. Regulation is achieved by cross-talk between Src family PTKs and CD19; Lyn is essential for CD19 phosphorylation, while CD19 establishes an Src family PTK activation loop that amplifies kinase activity. However, CD19-deficient (CD19(-/-)) B cells are hyporesponsive to transmembrane signals, while Lyn-deficient (Lyn(-/-)) B cells exhibit a hyper-responsive phenotype resulting in autoimmunity. To identify the outcome of interactions between CD19 and Src family PTKs in vivo, B cell function was examined in mice deficient for CD19 and Lyn (CD19/Lyn(-/-)). Remarkably, CD19 deficiency suppressed the hyper-responsive phenotype of Lyn(-/-) B cells and autoimmunity characterized by serum autoantibodies and immune complex-mediated glomerulonephritis in Lyn(-/-) mice. Consistent with Lyn and CD19 each regulating conventional B cell development, B1 cell development was markedly reduced by Lyn deficiency, with further reductions in the absence of CD19 expression. Tyrosine phosphorylation of Fyn and other cellular proteins induced following B cell Ag receptor ligation was dramatically reduced in CD19/Lyn(-/-) B cells relative to Lyn(-/-) B cells, while Syk phosphorylation was normal. In addition, the enhanced intracellular Ca(2+) responses following B cell Ag receptor ligation that typify Lyn deficiency were delayed by the loss of CD19 expression. BCR-induced proliferation and humoral immune responses were also markedly inhibited by CD19/Lyn deficiency. These findings demonstrate that while the CD19/Lyn amplification loop is a major regulator of signal transduction thresholds in B lymphocytes, CD19 regulation of other Src family PTKs also influences B cell function and the development of autoimmunity.
Hasegawa
M
M
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Fujimoto
M
M
Poe
J C
JC
Steeber
D A
DA
Lowell
C A
CA
Tedder
T F
TF
D000818:Animals; D000917:Antibody Formation; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism*; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D020013:Calcium Signaling; D002454:Cell Differentiation; D007075:Immunoglobulin M / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D015854:Up-Regulation; D019061:src-Family Kinases / Q000172:deficiency* / Q000235:genetics / Q000276:immunology*
D018941:Antigens, CD19; D007075:Immunoglobulin M; D011518:Proto-Oncogene Proteins; D011947:Receptors, Antigen, B-Cell; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases