CD19 Amplification of B Lymphocyte Ca2+ Responses

B lymphocyte antigen receptor (BCR) signals are regulated by CD19, with BCR-induced intracellular calcium ([Ca2+]i ) responses enhanced by CD19 co-ligation. In this study, CD19 engagement using a dimeric anti-CD19 antibody induced [Ca2+]i mobilization and significantly enhanced BCR-induced [Ca2+]i responses without a requirement for CD19/BCR co-ligation. Although simultaneous CD19 and BCR engagement significantly enhanced CD19/Lyn complex formation and [Ca2+]i responses, downstream tyrosine phosphorylation of CD22 and multiple other cellular proteins was inhibited, as was SHP1 recruitment to phosphorylated CD22. CD19 overexpression also enhanced BCR-induced [Ca2+]i responses, but down-regulated tyrosine phosphorylation of CD22 and multiple other cellular proteins following BCR ligation. Because CD19 and Lyn expression are genetically titrated in B cells, CD19 engagement may augment BCR-induced [Ca2+]i responses by sequestering the available pool of functional Lyn away from downstream negative regulatory proteins such as CD22. Consistent with this, simultaneous CD19 engagement did not further enhance the BCR-induced [Ca2+]i responses of Lyn- or CD22-deficient B cells. Thus, CD19 recruitment of Lyn may preferentially activate selective signaling pathways downstream of the CD19/Lyn complex to the exclusion of other downstream regulatory and effector pathways. Other receptors may also utilize a similar strategy to regulate kinase availability and downstream intermolecular signaling. B lymphocyte antigen receptor (BCR) signals are regulated by CD19, with BCR-induced intracellular calcium ([Ca2+]i ) responses enhanced by CD19 co-ligation. In this study, CD19 engagement using a dimeric anti-CD19 antibody induced [Ca2+]i mobilization and significantly enhanced BCR-induced [Ca2+]i responses without a requirement for CD19/BCR co-ligation. Although simultaneous CD19 and BCR engagement significantly enhanced CD19/Lyn complex formation and [Ca2+]i responses, downstream tyrosine phosphorylation of CD22 and multiple other cellular proteins was inhibited, as was SHP1 recruitment to phosphorylated CD22. CD19 overexpression also enhanced BCR-induced [Ca2+]i responses, but down-regulated tyrosine phosphorylation of CD22 and multiple other cellular proteins following BCR ligation. Because CD19 and Lyn expression are genetically titrated in B cells, CD19 engagement may augment BCR-induced [Ca2+]i responses by sequestering the available pool of functional Lyn away from downstream negative regulatory proteins such as CD22. Consistent with this, simultaneous CD19 engagement did not further enhance the BCR-induced [Ca2+]i responses of Lyn- or CD22-deficient B cells. Thus, CD19 recruitment of Lyn may preferentially activate selective signaling pathways downstream of the CD19/Lyn complex to the exclusion of other downstream regulatory and effector pathways. Other receptors may also utilize a similar strategy to regulate kinase availability and downstream intermolecular signaling. B lymphocyte antigen receptor intracellular calcium concentration transgenic mice expressing a human CD19 transgene extracellular signal-regulated kinase horseradish peroxidase mitogen-activated protein kinase polyacrylamide gel electrophoresis phosphatidylinositol 3-kinase phospholipase C SHIP, Src homology-2 domain-containing inositol polyphosphate-5′ phosphatase Src homology-2-containing protein-tyrosine phosphatase-1 monoclonal antibody fluorescein isothiocyanate B lymphocyte development and function are regulated by signals transduced through the B cell antigen receptor (BCR)1 and cell surface regulatory molecules including CD19 (1Tedder T.F. Inaoki M. Sato S. Immunity. 1997; 6: 107-118Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, 2Fearon D.T. Locksley R.M. Science. 1996; 272: 50-54Crossref PubMed Scopus (1427) Google Scholar, 3Buhl A.M. Cambier J.C. Immunol. Rev. 1997; 160: 127-138Crossref PubMed Scopus (38) Google Scholar). CD19 is a member of the immunoglobulin superfamily expressed exclusively on B cells and follicular dendritic cells (4Tedder T.F. Isaacs C.M. J. Immunol. 1989; 143: 712-717PubMed Google Scholar). CD19 has a ∼240-amino acid cytoplasmic domain that is critical for CD19 signaling (4Tedder T.F. Isaacs C.M. J. Immunol. 1989; 143: 712-717PubMed Google Scholar, 5Bradbury L.E. Goldmacher V.S. Tedder T.F. J. Immunol. 1993; 151: 2915-2927PubMed Google Scholar, 6Sato S. Miller A.S. Howard M.C. Tedder T.F. J. Immunol. 1997; 159: 3278-3287PubMed Google Scholar), and CD19-deficient (CD19−/−) mice are hyporesponsive to a variety of transmembrane signals (7Engel P. Zhou L.-J. Ord D.C. Sato S. Koller B. Tedder T.F. Immunity. 1995; 3: 39-50Abstract Full Text PDF PubMed Scopus (484) Google Scholar, 8Rickert R.C. Rajewsky K. Roes J. Nature. 1995; 376: 352-355Crossref PubMed Scopus (578) Google Scholar, 9Sato S. Steeber D.A. Tedder T.F. Proc. Natl. Acad. Sci. U. S. A. 1995; PubMed Scopus Google Scholar). CD19 as a protein for the of Src protein-tyrosine kinase and as for multiple signaling pathways for and antigen signals M. J.C. Inaoki M. Tedder T.F. Immunol. PubMed Scopus Google Scholar, M. J.C. Tedder T.F. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar, M. J.C. Sato S. Tedder T.F. J. Immunol. Google Scholar). cytoplasmic of human CD19 and CD19 are L.-J. Ord D.C. Tedder T.F. J. Immunol. Google Scholar). In human CD19 CD19 function expressed the in mice S. Steeber D.A. Tedder T.F. J. Immunol. 1997; Google Scholar). of CD19 in transgenic mice expressing a human CD19 transgene B cells to transmembrane signals and Thus, CD19 is a of B cell function Src mitogen-activated protein kinase and and CD19 and BCR BCR-induced ([Ca2+]i ) responses D.A. D.T. J. Immunol. Google and the for B cell D.T. Science. PubMed Scopus Google Scholar, S. D.T. Science. 1996; PubMed Scopus Google CD19 and BCR significantly enhance [Ca2+]i responses D.T. Science. PubMed Scopus Google Scholar, D.A. D.T. J. Immunol. Google Scholar), is CD19 augment BCR-induced [Ca2+]i responses of BCR and CD19 CD19 also BCR-induced [Ca2+]i responses and B cell A. B. J. Immunol. Google Scholar, A. J. Immunol. PubMed Scopus (38) Google Scholar, S. J. Immunol. Google Scholar, J. Immunol. PubMed Scopus Google Scholar, Immunol. 1989; PubMed Scopus Google Scholar). Although the through CD19 or BCR-induced [Ca2+]i responses are the that the or of CD19 may to a and negative regulatory signals and signals transduced the a dimeric CD19 monoclonal antibody S. Steeber D.A. Tedder T.F. J. Immunol. 1996; Google that of the functional of CD19 of BCR ligation. CD19 and BCR engagement was to augment BCR-induced [Ca2+]i responses and regulate BCR signaling through on the or of CD19 that pathways by CD19 and BCR to [Ca2+]i responses and without a requirement for a CD19 signaling of B cells of antigen receptor engagement or of antigen receptor (1Tedder T.F. Inaoki M. Sato S. Immunity. 1997; 6: 107-118Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, T.F. Immunol. PubMed Scopus Google Scholar). is by the of CD19-deficient and mice (1Tedder T.F. Inaoki M. Sato S. Immunity. 1997; 6: 107-118Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar). Although and to CD19 and to the of the CD19 complex are the for the CD19 complex and the of CD19 to signaling without a requirement for with the BCR complex that CD19 may regulate B cell function of antigen the that simultaneous CD19 and BCR in in B cell protein-tyrosine phosphorylation to phosphorylation induced by was BCR-induced protein-tyrosine phosphorylation was also in B cells from mice that CD19 Consistent with this, simultaneous BCR and CD19 tyrosine phosphorylation S. Tedder T.F. Proc. Natl. Acad. U. S. A. 1997; PubMed Scopus Google Scholar), BCR or CD19 phosphorylation and complex formation M. D.T. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Full Text PDF PubMed Google Scholar, S. Tedder T.F. Proc. Natl. Acad. U. S. A. 1997; PubMed Scopus Google Scholar). Thus, B cell kinase simultaneous CD19 kinase pathways downstream of BCR that CD19 Src and and that phosphorylated CD19 preferentially and a for simultaneous BCR and CD19 [Ca2+]i responses B cell protein-tyrosine phosphorylation the Src in B cells, preferentially and a critical in CD19, and CD22 function Immunol. PubMed Scopus Google Scholar). Because CD19, and Lyn expression are genetically titrated in B cells P. M. M. A. Tedder T.F. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), BCR signaling is significantly by in the expression and functional of molecules and Lyn and other Src following BCR engagement with to phosphorylated CD19 and the BCR M. J.C. Tedder T.F. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar, C.M. S. 1993; PubMed Scopus Google Scholar, B. J. 1993; Full Text PDF PubMed Google Scholar, Immunol. 1993; PubMed Scopus Google Scholar, M. M. J.C. Steeber D.A. Tedder T.F. J. Immunol. PubMed Scopus Google Scholar). In phosphorylated CD19 as protein for Lyn and the of Src and In with this, simultaneous CD19 engagement BCR signaling significantly CD19/Lyn complex formation CD19 is to regulate the of Lyn the Lyn and CD19 preferentially and of the CD19 complex in a of CD19 of BCR and of phosphorylated CD19 to and CD19/Lyn may Lyn to a that multiple downstream signaling pathways and CD22 phosphorylation are M. J.C. Tedder T.F. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar, M. J.C. Steeber D.A. Tedder T.F. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar). Although the of Lyn with CD19 a of cellular Lyn M. J.C. Tedder T.F. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar), the of cellular Lyn that is or available for the CD19 or BCR signaling pathways is in the available pool of Lyn may of Consistent with the that CD19 [Ca2+]i responses by sequestering Lyn away from CD22 and other negative regulatory BCR-induced [Ca2+]i responses are significantly enhanced in B cells Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, CD19, and Lyn are to to regulate [Ca2+]i responses and B cell molecules in BCR-induced [Ca2+]i responses 3-kinase and are to or regulated by CD19 D.A. D.T. Science. 1993; PubMed Scopus Google Scholar, M. J.C. Steeber D.A. Tedder T.F. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar). 3-kinase not to the by CD19 BCR signaling 3-kinase did not the of CD19 to augment BCR-induced [Ca2+]i responses that CD19 may enhance BCR-induced [Ca2+]i responses by sequestering Lyn and selective downstream signaling including CD22 phosphorylation In of this, Lyn is for CD22 phosphorylation J.C. M. Miller A.S. Tedder T.F. J. Full Text Full Text PDF PubMed Scopus Google Scholar, Immunol. PubMed Scopus Google and CD19 BCR engagement down-regulated CD22 phosphorylation and SHP1 recruitment by CD22 In BCR-induced [Ca2+]i responses enhanced in B cells that CD19 CD22 phosphorylation and SHP1 recruitment by CD22 following BCR C and BCR-induced [Ca2+]i responses are a of CD22-deficient B cells S. Miller A.S. Inaoki M. Tedder T.F. Immunity. 1996; Full Text PDF PubMed Scopus Google Scholar, B. M.C. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Science. 1996; PubMed Scopus Google Scholar, R.M. Nature. 1996; PubMed Scopus Google Scholar), but BCR-induced [Ca2+]i responses in or B cells not by simultaneous CD19 Although CD22 on B cell [Ca2+]i responses, CD22 is to recruitment of the SHP1 and and Lyn is to a for SHP1 A. K. J. J. Full Text Full Text PDF PubMed Scopus Google Scholar), with the that Lyn phosphorylation may by simultaneous CD19 and BCR engagement Thus, simultaneous CD19 and BCR engagement may augment Lyn through multiple CD19 of Lyn kinase CD22 and SHP1 and to CD22. CD22 may also from may enhance CD19/Lyn phosphorylation proteins following CD19 Consistent with CD19 phosphorylation was following BCR or simultaneous CD19 and BCR in B cells. J. and Thus, the of CD19 to phosphorylation of and other negative regulatory may enhance CD19 was to a and negative of BCR CD19 augment or BCR signaling and [Ca2+]i responses A. B. J. Immunol. Google Scholar, A. J. Immunol. PubMed Scopus (38) Google Scholar, S. J. Immunol. Google Scholar, J. Immunol. PubMed Scopus Google Scholar). Consistent with this, CD19 BCR-induced [Ca2+]i responses, [Ca2+]i responses B and In with the of the CD19 complex are of B cell S. Rev. Immunol. PubMed Scopus Google Scholar). Thus, CD19 may and negative on of CD19 may the available pool of functional Lyn and phosphorylation not induced CD19 was using anti-CD19 antibody and phosphorylated to induced by CD19 and not CD19 BCR-induced [Ca2+]i responses in the of CD22 expression CD19 BCR-induced [Ca2+]i responses in B cells may by the that CD19 and Src in to Lyn and CD19 by antibody may CD19 away from the BCR complex and signaling. this is the that tyrosine phosphorylation of cellular proteins was in CD19 B cells following BCR engagement in the of CD19 CD19 with antibody BCR-induced [Ca2+]i responses to the induced by CD19 Because [Ca2+]i responses are in CD19-deficient B cells S. Steeber D.A. Tedder T.F. J. Immunol. 1997; Google Scholar), is not antibody of CD19 away from a on BCR-induced [Ca2+]i responses the of Thus, CD19 may Lyn and other Src to a that multiple downstream signaling pathways for [Ca2+]i responses are that CD19 engagement may the of signaling without a requirement for of receptor of CD19 to Lyn kinase and in with to CD22 negative may with BCR Thus, the that the CD19, and other and negative regulatory cell surface proteins may on and other receptor by or a pool of of a of Lyn in cells is a for function Science. PubMed Scopus Google Scholar). other receptors are to of downstream effector molecules engagement and may utilize a similar strategy to regulate intermolecular signaling and the of downstream pathways. B lymphocyte development and function are regulated by signals transduced through the B cell antigen receptor (BCR)1 and cell surface regulatory molecules including CD19 (1Tedder T.F. Inaoki M. Sato S. Immunity. 1997; 6: 107-118Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, 2Fearon D.T. Locksley R.M. Science. 1996; 272: 50-54Crossref PubMed Scopus (1427) Google Scholar, 3Buhl A.M. Cambier J.C. Immunol. Rev. 1997; 160: 127-138Crossref PubMed Scopus (38) Google Scholar). CD19 is a member of the immunoglobulin superfamily expressed exclusively on B cells and follicular dendritic cells (4Tedder T.F. Isaacs C.M. J. Immunol. 1989; 143: 712-717PubMed Google Scholar). CD19 has a ∼240-amino acid cytoplasmic domain that is critical for CD19 signaling (4Tedder T.F. Isaacs C.M. J. Immunol. 1989; 143: 712-717PubMed Google Scholar, 5Bradbury L.E. Goldmacher V.S. Tedder T.F. J. Immunol. 1993; 151: 2915-2927PubMed Google Scholar, 6Sato S. Miller A.S. Howard M.C. Tedder T.F. J. Immunol. 1997; 159: 3278-3287PubMed Google Scholar), and CD19-deficient (CD19−/−) mice are hyporesponsive to a variety of transmembrane signals (7Engel P. Zhou L.-J. Ord D.C. Sato S. Koller B. Tedder T.F. Immunity. 1995; 3: 39-50Abstract Full Text PDF PubMed Scopus (484) Google Scholar, 8Rickert R.C. Rajewsky K. Roes J. Nature. 1995; 376: 352-355Crossref PubMed Scopus (578) Google Scholar, 9Sato S. Steeber D.A. Tedder T.F. Proc. Natl. Acad. Sci. U. S. A. 1995; PubMed Scopus Google Scholar). CD19 as a protein for the of Src protein-tyrosine kinase and as for multiple signaling pathways for and antigen signals M. J.C. Inaoki M. Tedder T.F. Immunol. PubMed Scopus Google Scholar, M. J.C. Tedder T.F. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar, M. J.C. Sato S. Tedder T.F. J. Immunol. Google Scholar). cytoplasmic of human CD19 and CD19 are L.-J. Ord D.C. Tedder T.F. J. Immunol. Google Scholar). In human CD19 CD19 function expressed the in mice S. Steeber D.A. Tedder T.F. J. Immunol. 1997; Google Scholar). of CD19 in transgenic mice expressing a human CD19 transgene B cells to transmembrane signals and Thus, CD19 is a of B cell function Src mitogen-activated protein kinase and and CD19 and BCR BCR-induced ([Ca2+]i ) responses D.A. D.T. J. Immunol. Google and the for B cell D.T. Science. PubMed Scopus Google Scholar, S. D.T. Science. 1996; PubMed Scopus Google Scholar). Although CD19 and BCR significantly enhance [Ca2+]i responses D.T. Science. PubMed Scopus Google Scholar, D.A. D.T. J. Immunol. Google Scholar), is CD19 augment BCR-induced [Ca2+]i responses of BCR and CD19 CD19 also BCR-induced [Ca2+]i responses and B cell A. B. J. Immunol. Google Scholar, A. J. Immunol. PubMed Scopus (38) Google Scholar, S. J. Immunol. Google Scholar, J. Immunol. PubMed Scopus Google Scholar, Immunol. 1989; PubMed Scopus Google Scholar). Although the through CD19 or BCR-induced [Ca2+]i responses are the that the or of CD19 may to a and negative regulatory signals and signals transduced the a dimeric CD19 monoclonal antibody S. Steeber D.A. Tedder T.F. J. Immunol. 1996; Google that of the functional of CD19 of BCR ligation. CD19 and BCR engagement was to augment BCR-induced [Ca2+]i responses and regulate BCR signaling through on the or of CD19 ligation. that pathways by CD19 and BCR to [Ca2+]i responses and without a requirement for a CD19 signaling of B cells of antigen receptor engagement or of antigen receptor (1Tedder T.F. Inaoki M. Sato S. Immunity. 1997; 6: 107-118Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, T.F. Immunol. PubMed Scopus Google Scholar). is by the of CD19-deficient and mice (1Tedder T.F. Inaoki M. Sato S. Immunity. 1997; 6: 107-118Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar). Although and to CD19 and to the of the CD19 complex are the for the CD19 complex and the of CD19 to signaling without a requirement for with the BCR complex that CD19 may regulate B cell function of antigen the that simultaneous CD19 and BCR in in B cell protein-tyrosine phosphorylation to phosphorylation induced by was BCR-induced protein-tyrosine phosphorylation was also in B cells from mice that CD19 Consistent with this, simultaneous BCR and CD19 tyrosine phosphorylation S. Tedder T.F. Proc. Natl. Acad. U. S. A. 1997; PubMed Scopus Google Scholar), BCR or CD19 phosphorylation and complex formation M. D.T. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Full Text PDF PubMed Google Scholar, S. Tedder T.F. Proc. Natl. Acad. U. S. A. 1997; PubMed Scopus Google Scholar). Thus, B cell kinase simultaneous CD19 kinase pathways downstream of BCR that CD19 Src and and that phosphorylated CD19 preferentially and a for simultaneous BCR and CD19 [Ca2+]i responses B cell protein-tyrosine phosphorylation the Src in B cells, preferentially and a critical in CD19, and CD22 function Immunol. PubMed Scopus Google Scholar). Because CD19, and Lyn expression are genetically titrated in B cells P. M. M. A. Tedder T.F. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), BCR signaling is significantly by in the expression and functional of molecules and Lyn and other Src following BCR engagement with to phosphorylated CD19 and the BCR M. J.C. Tedder T.F. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar, C.M. S. 1993; PubMed Scopus Google Scholar, B. J. 1993; Full Text PDF PubMed Google Scholar, Immunol. 1993; PubMed Scopus Google Scholar, M. M. J.C. Steeber D.A. Tedder T.F. J. Immunol. PubMed Scopus Google Scholar). In phosphorylated CD19 as protein for Lyn and the of Src and In with this, simultaneous CD19 engagement BCR signaling significantly CD19/Lyn complex formation CD19 is to regulate the of Lyn the Lyn and CD19 preferentially and of the CD19 complex in a of CD19 of BCR and of phosphorylated CD19 to and CD19/Lyn may Lyn to a that multiple downstream signaling pathways and CD22 phosphorylation are M. J.C. Tedder T.F. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar, M. J.C. Steeber D.A. Tedder T.F. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar). Although the of Lyn with CD19 a of cellular Lyn M. J.C. Tedder T.F. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar), the of cellular Lyn that is or available for the CD19 or BCR signaling pathways is in the available pool of Lyn may of Consistent with the that CD19 [Ca2+]i responses by sequestering Lyn away from CD22 and other negative regulatory BCR-induced [Ca2+]i responses are significantly enhanced in B cells Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, CD19, and Lyn are to to regulate [Ca2+]i responses and B cell molecules in BCR-induced [Ca2+]i responses 3-kinase and are to or regulated by CD19 D.A. D.T. Science. 1993; PubMed Scopus Google Scholar, M. J.C. Steeber D.A. Tedder T.F. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar). 3-kinase not to the by CD19 BCR signaling 3-kinase did not the of CD19 to augment BCR-induced [Ca2+]i responses that CD19 may enhance BCR-induced [Ca2+]i responses by sequestering Lyn and selective downstream signaling including CD22 phosphorylation In of this, Lyn is for CD22 phosphorylation J.C. M. Miller A.S. Tedder T.F. J. Full Text Full Text PDF PubMed Scopus Google Scholar, Immunol. PubMed Scopus Google and CD19 BCR engagement down-regulated CD22 phosphorylation and SHP1 recruitment by CD22 In BCR-induced [Ca2+]i responses enhanced in B cells that CD19 CD22 phosphorylation and SHP1 recruitment by CD22 following BCR C and BCR-induced [Ca2+]i responses are a of CD22-deficient B cells S. Miller A.S. Inaoki M. Tedder T.F. Immunity. 1996; Full Text PDF PubMed Scopus Google Scholar, B. M.C. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Science. 1996; PubMed Scopus Google Scholar, R.M. Nature. 1996; PubMed Scopus Google Scholar), but BCR-induced [Ca2+]i responses in or B cells not by simultaneous CD19 Although CD22 on B cell [Ca2+]i responses, CD22 is to recruitment of the SHP1 and and Lyn is to a for SHP1 A. K. J. J. Full Text Full Text PDF PubMed Scopus Google Scholar), with the that Lyn phosphorylation may by simultaneous CD19 and BCR engagement Thus, simultaneous CD19 and BCR engagement may augment Lyn through multiple CD19 of Lyn kinase CD22 and SHP1 and to CD22. CD22 may also from may enhance CD19/Lyn phosphorylation proteins following CD19 Consistent with CD19 phosphorylation was following BCR or simultaneous CD19 and BCR in B cells. J. and Thus, the of CD19 to phosphorylation of and other negative regulatory may enhance CD19 was to a and negative of BCR CD19 augment or BCR signaling and [Ca2+]i responses A. B. J. Immunol. Google Scholar, A. J. Immunol. PubMed Scopus (38) Google Scholar, S. J. Immunol. Google Scholar, J. Immunol. PubMed Scopus Google Scholar). Consistent with this, CD19 BCR-induced [Ca2+]i responses, [Ca2+]i responses B and In with the of the CD19 complex are of B cell S. Rev. Immunol. PubMed Scopus Google Scholar). Thus, CD19 may and negative on of CD19 may the available pool of functional Lyn and phosphorylation not induced CD19 was using anti-CD19 antibody and phosphorylated to induced by CD19 and not CD19 BCR-induced [Ca2+]i responses in the of CD22 expression CD19 BCR-induced [Ca2+]i responses in B cells may by the that CD19 and Src in to Lyn and CD19 by antibody may CD19 away from the BCR complex and signaling. this is the that tyrosine phosphorylation of cellular proteins was in CD19 B cells following BCR engagement in the of CD19 CD19 with antibody BCR-induced [Ca2+]i responses to the induced by CD19 Because [Ca2+]i responses are in CD19-deficient B cells S. Steeber D.A. Tedder T.F. J. Immunol. 1997; Google Scholar), is not antibody of CD19 away from a on BCR-induced [Ca2+]i responses the of Thus, CD19 may Lyn and other Src to a that multiple downstream signaling pathways for [Ca2+]i responses are that CD19 engagement may the of signaling without a requirement for of receptor of CD19 to Lyn kinase and in with to CD22 negative may with BCR Thus, the that the CD19, and other and negative regulatory cell surface proteins may on and other receptor by or a pool of of a of Lyn in cells is a for function Science. PubMed Scopus Google Scholar). other receptors are to of downstream effector molecules engagement and may utilize a similar strategy to regulate intermolecular signaling and the of downstream pathways. that pathways by CD19 and BCR to [Ca2+]i responses and without a requirement for a CD19 signaling of B cells of antigen receptor engagement or of antigen receptor (1Tedder T.F. Inaoki M. Sato S. Immunity. 1997; 6: 107-118Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, T.F. Immunol. PubMed Scopus Google Scholar). is by the of CD19-deficient and mice (1Tedder T.F. Inaoki M. Sato S. Immunity. 1997; 6: 107-118Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar). Although and to CD19 and to the of the CD19 complex are the for the CD19 complex and the of CD19 to signaling without a requirement for with the BCR complex that CD19 may regulate B cell function of antigen the that simultaneous CD19 and BCR in in B cell protein-tyrosine phosphorylation to phosphorylation induced by was BCR-induced protein-tyrosine phosphorylation was also in B cells from mice that CD19 Consistent with this, simultaneous BCR and CD19 tyrosine phosphorylation S. Tedder T.F. Proc. Natl. Acad. U. S. A. 1997; PubMed Scopus Google Scholar), BCR or CD19 phosphorylation and complex formation M. D.T. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Full Text PDF PubMed Google Scholar, S. Tedder T.F. Proc. Natl. Acad. U. S. A. 1997; PubMed Scopus Google Scholar). Thus, B cell kinase simultaneous CD19 kinase pathways downstream of BCR that CD19 Src and and that phosphorylated CD19 preferentially and a for simultaneous BCR and CD19 [Ca2+]i responses B cell protein-tyrosine phosphorylation the Src in B cells, preferentially and a critical in CD19, and CD22 function Immunol. PubMed Scopus Google Scholar). Because CD19, and Lyn expression are genetically titrated in B cells P. M. M. A. Tedder T.F. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), BCR signaling is significantly by in the expression and functional of molecules and Lyn and other Src following BCR engagement with to phosphorylated CD19 and the BCR M. J.C. Tedder T.F. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar, C.M. S. 1993; PubMed Scopus Google Scholar, B. J. 1993; Full Text PDF PubMed Google Scholar, Immunol. 1993; PubMed Scopus Google Scholar, M. M. J.C. Steeber D.A. Tedder T.F. J. Immunol. PubMed Scopus Google Scholar). In phosphorylated CD19 as protein for Lyn and the of Src and In with this, simultaneous CD19 engagement BCR signaling significantly CD19/Lyn complex formation CD19 is to regulate the of Lyn the Lyn and CD19 preferentially and of the CD19 complex in a of CD19 of BCR and of phosphorylated CD19 to and CD19/Lyn may Lyn to a that multiple downstream signaling pathways and CD22 phosphorylation are M. J.C. Tedder T.F. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar, M. J.C. Steeber D.A. Tedder T.F. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar). Although the of Lyn with CD19 a of cellular Lyn M. J.C. Tedder T.F. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar), the of cellular Lyn that is or available for the CD19 or BCR signaling pathways is in the available pool of Lyn may of Consistent with the that CD19 [Ca2+]i responses by sequestering Lyn away from CD22 and other negative regulatory BCR-induced [Ca2+]i responses are significantly enhanced in B cells Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, CD19, and Lyn are to to regulate [Ca2+]i responses and B cell molecules in BCR-induced [Ca2+]i responses 3-kinase and are to or regulated by CD19 D.A. D.T. Science. 1993; PubMed Scopus Google Scholar, M. J.C. Steeber D.A. Tedder T.F. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar). 3-kinase not to the by CD19 BCR signaling 3-kinase did not the of CD19 to augment BCR-induced [Ca2+]i responses that CD19 may enhance BCR-induced [Ca2+]i responses by sequestering Lyn and selective downstream signaling including CD22 phosphorylation In of this, Lyn is for CD22 phosphorylation J.C. M. Miller A.S. Tedder T.F. J. Full Text Full Text PDF PubMed Scopus Google Scholar, Immunol. PubMed Scopus Google and CD19 BCR engagement down-regulated CD22 phosphorylation and SHP1 recruitment by CD22 In BCR-induced [Ca2+]i responses enhanced in B cells that CD19 CD22 phosphorylation and SHP1 recruitment by CD22 following BCR C and BCR-induced [Ca2+]i responses are a of CD22-deficient B cells S. Miller A.S. Inaoki M. Tedder T.F. Immunity. 1996; Full Text PDF PubMed Scopus Google Scholar, B. M.C. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Science. 1996; PubMed Scopus Google Scholar, R.M. Nature. 1996; PubMed Scopus Google Scholar), but BCR-induced [Ca2+]i responses in or B cells not by simultaneous CD19 Although CD22 on B cell [Ca2+]i responses, CD22 is to recruitment of the SHP1 and and Lyn is to a for SHP1 A. K. J. J. Full Text Full Text PDF PubMed Scopus Google Scholar), with the that Lyn phosphorylation may by simultaneous CD19 and BCR engagement Thus, simultaneous CD19 and BCR engagement may augment Lyn through multiple CD19 of Lyn kinase CD22 and SHP1 and to CD22. CD22 may also from may enhance CD19/Lyn phosphorylation proteins following CD19 Consistent with CD19 phosphorylation was following BCR or simultaneous CD19 and BCR in B cells. J. and Thus, the of CD19 to phosphorylation of and other negative regulatory may enhance CD19 CD19 was to a and negative of BCR CD19 augment or BCR signaling and [Ca2+]i responses A. B. J. Immunol. Google Scholar, A. J. Immunol. PubMed Scopus (38) Google Scholar, S. J. Immunol. Google Scholar, J. Immunol. PubMed Scopus Google Scholar). Consistent with this, CD19 BCR-induced [Ca2+]i responses, [Ca2+]i responses B and In with the of the CD19 complex are of B cell S. Rev. Immunol. PubMed Scopus Google Scholar). Thus, CD19 may and negative on of CD19 may the available pool of functional Lyn and phosphorylation not induced CD19 was using anti-CD19 antibody and phosphorylated to induced by CD19 and not CD19 BCR-induced [Ca2+]i responses in the of CD22 expression CD19 BCR-induced [Ca2+]i responses in B cells may by the that CD19 and Src in to Lyn and CD19 by antibody may CD19 away from the BCR complex and signaling. this is the that tyrosine phosphorylation of cellular proteins was in CD19 B cells following BCR engagement in the of CD19 CD19 with antibody BCR-induced [Ca2+]i responses to the induced by CD19 Because [Ca2+]i responses are in CD19-deficient B cells S. Steeber D.A. Tedder T.F. J. Immunol. 1997; Google Scholar), is not antibody of CD19 away from a on BCR-induced [Ca2+]i responses the of Thus, CD19 may Lyn and other Src to a that multiple downstream signaling pathways for [Ca2+]i responses are that CD19 engagement may the of signaling without a requirement for of receptor of CD19 to Lyn kinase and in with to CD22 negative may with BCR Thus, the that the CD19, and other and negative regulatory cell surface proteins may on and other receptor by or a pool of of a of Lyn in cells is a for function Science. PubMed Scopus Google Scholar). other receptors are to of downstream effector molecules engagement and may utilize a similar strategy to regulate intermolecular signaling and the of downstream pathways. M. and for mice and for