title: A balance between B cell receptor and inhibitory receptor signaling controls plasma cell differentiation by maintaining optimal Ets1 levels.
abstract: Signaling through the BCR can drive B cell activation and contribute to B cell differentiation into Ab-secreting plasma cells. The positive BCR signal is counterbalanced by a number of membrane-localized inhibitory receptors that limit B cell activation and plasma cell differentiation. Deficiencies in these negative signaling pathways may cause autoantibody generation and autoimmune disease in both animal models and human patients. We have previously shown that the transcription factor Ets1 can restrain B cell differentiation into plasma cells. In this study, we tested the roles of the BCR and inhibitory receptors in controlling the expression of Ets1 in mouse B cells. We found that Ets1 is downregulated in B cells by BCR or TLR signaling through a pathway dependent on PI3K, Btk, IKK2, and JNK. Deficiencies in inhibitory pathways, such as a loss of the tyrosine kinase Lyn, the phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP1) or membrane receptors CD22 and/or Siglec-G, result in enhanced BCR signaling and decreased Ets1 expression. Restoring Ets1 expression in Lyn- or SHP1-deficient B cells inhibits their enhanced plasma cell differentiation. Our findings indicate that downregulation of Ets1 occurs in response to B cell activation via either BCR or TLR signaling, thereby allowing B cell differentiation and that the maintenance of Ets1 expression is an important function of the inhibitory Lyn → CD22/SiglecG → SHP1 pathway in B cells.
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203.
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203.
authors.forename: Jessica
authors.initials: J
authors.lastname: Mayeux
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203.
authors.forename: Toni
authors.initials: T
authors.lastname: Gutierrez
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203.
authors.forename: Lisa
authors.initials: L
authors.lastname: Russell
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203.
authors.forename: Andrew
authors.initials: A
authors.lastname: Getahun
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Müller
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tedder
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203.
authors.forename: Jane
authors.initials: J
authors.lastname: Parnes
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203.
authors.forename: Robert
authors.initials: R
authors.lastname: Rickert
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203.
authors.forename: Lars
authors.initials: L
authors.lastname: Nitschke
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203.
authors.forename: John
authors.initials: J
authors.lastname: Cambier
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Satterthwaite
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203.
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: Garrett-Sinha
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000276:immunology; D037102:Lectins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology* / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000276:immunology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000276:immunology
chemical_list: D000077329:Agammaglobulinaemia Tyrosine Kinase; D037102:Lectins; D019869:Phosphatidylinositol 3-Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D011505:Protein-Tyrosine Kinases; D050784:Proto-Oncogene Protein c-ets-1; D011947:Receptors, Antigen, B-Cell; D011956:Receptors, Cell Surface; D051918:Sialic Acid Binding Ig-like Lectin 2; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D019061:src-Family Kinases; C494042:Ets1 protein, mouse; C522403:Siglecg protein, mouse; C000625949:BTK protein, human; C060902:lyn protein-tyrosine kinase