Developmental acquisition of the Lyn-CD22-SHP-1 inhibitory pathway promotes B cell tolerance.
To better understand whether autoimmunity in Lyn-deficient mice arises from compromised central or peripheral B cell tolerance, we examined BCR signaling properties of wild-type and Lyn-deficient B cells at different stages of development. Wild-type mature follicular B cells were less sensitive to BCR stimulation than were immature transitional stage 1 B cells with regard to BCR-induced calcium elevation and ERK MAPK activation. In the absence of Lyn, mature B cell signaling was greatly enhanced, whereas immature B cell signaling was minimally affected. Correspondingly, Lyn deficiency substantially enhanced the sensitivity of mature B cells to activation via the BCR, but minimally affected events associated with tolerance induction at the immature stage. The effects of CD22 deficiency on BCR signaling were very similar in B cells at different stages of maturation. These results indicate that the Lyn-CD22-Src homology region 2 domain-containing phosphatase-1 inhibitory pathway largely becomes operational as B cell mature, and sets a threshold for activation that appears to be critical for the maintenance of tolerance in the B cell compartment.
Gross
Andrew J
AJ
Department of Medicine, University of California, San Francisco, CA 94143, USA.
Lyandres
Julia R
JR
Panigrahi
Anil K
AK
Prak
Eline T Luning
ET
DeFranco
Anthony L
AL
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D007108:Immune Tolerance / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology
C497868:Cd22 protein, mouse; D011947:Receptors, Antigen, B-Cell; D051918:Sialic Acid Binding Ig-like Lectin 2; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse