Original Article

Interference with Immunoglobulin (Ig) Immunoreceptor Tyrosine–based Activation Motif (ITAM) Phosphorylation Modulates or Blocks B Cell Development, Depending on the Availability of an Igß Cytoplasmic Tail

Correspondence to: Manfred Kraus, Harvard Medical School, 200 Longwood Ave., Boston, MA 02115. Tel:617-278-3274 Fax:617-278-3131 E-mail:kraus{at}cbr.med.harvard.edu.

To determine the function of immunoglobulin (Ig) immunoreceptor tyrosine–based activation motif (ITAM) phosphorylation, we generated mice in which Ig ITAM tyrosines were replaced by phenylalanines (Ig^FF/FF). Ig^FF/FF mice had a specific reduction of B1 and marginal zone B cells, whereas B2 cell development appeared to be normal, except that 1 light chain usage was increased. The mutants responded less efficiently to T cell–dependent antigens, whereas T cell–independent responses were unaffected. Upon B cell receptor ligation, the cells exhibited heightened calcium flux, weaker Lyn and Syk tyrosine phosphorylation, and phosphorylation of Ig non-ITAM tyrosines. Strikingly, when the Ig ITAM mutation was combined with a truncation of Igß, B cell development was completely blocked at the pro-B cell stage, indicating a crucial role of ITAM phosphorylation in B cell development.

Key Words: mb-1 protein, B cell antigen receptor, ITAM, B cell subsets, gene targeting

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Chen, X., Bai, F., Sokol, L., Zhou, J., Ren, A., Painter, J. S., Liu, J., Sallman, D. A., Chen, Y. A., Yoder, J. A., Djeu, J. Y., Loughran, T. P., Epling-Burnette, P. K., Wei, S. (2009). A critical role for DAP10 and DAP12 in CD8+ T cell-mediated tissue damage in large granular lymphocyte leukemia. Blood 113: 3226-3234 [Abstract] [Full Text]  
• Young, R. M., Hardy, I. R., Clarke, R. L., Lundy, N., Pine, P., Turner, B. C., Potter, T. A., Refaeli, Y. (2009). Mouse models of non-Hodgkin lymphoma reveal Syk as an important therapeutic target. Blood 113: 2508-2516 [Abstract] [Full Text]  
• Imai, Y., Park, E. J., Peer, D., Peixoto, A., Cheng, G., von Andrian, U. H., Carman, C. V., Shimaoka, M. (2008). Genetic perturbation of the putative cytoplasmic membrane-proximal salt bridge aberrantly activates {alpha}4 integrins. Blood 112: 5007-5015 [Abstract] [Full Text]  
• Epling-Burnette, P. K., Sokol, L., Chen, X., Bai, F., Zhou, J., Blaskovich, M. A., Zou, J., Painter, J. S., Edwards, T. D., Moscinski, L., Yoder, J. A., Djeu, J. Y., Sebti, S., Loughran, T. P. Jr, Wei, S. (2008). Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling. Blood 112: 4694-4698 [Abstract] [Full Text]  
• Dobbs, A. K., Yang, T., Farmer, D., Kager, L., Parolini, O., Conley, M. E. (2007). Cutting Edge: A Hypomorphic Mutation in Igbeta (CD79b) in a Patient with Immunodeficiency and a Leaky Defect in B Cell Development. J. Immunol. 179: 2055-2059 [Abstract] [Full Text]  
• Waisman, A., Kraus, M., Seagal, J., Ghosh, S., Melamed, D., Song, J., Sasaki, Y., Classen, S., Lutz, C., Brombacher, F., Nitschke, L., Rajewsky, K. (2007). IgG1 B cell receptor signaling is inhibited by CD22 and promotes the development of B cells whose survival is less dependent on Ig{alpha}/{beta}. JEM 204: 747-758 [Abstract] [Full Text]  
• Song, H., Zhang, J., Chiang, Y. J., Siraganian, R. P., Hodes, R. J. (2007). Redundancy in B Cell Developmental Pathways: c-Cbl Inactivation Rescues Early B Cell Development through a B Cell Linker Protein-Independent Pathway. J. Immunol. 178: 926-935 [Abstract] [Full Text]  
• Fuentes-Panana, E. M., Bannish, G., Karnell, F. G., Treml, J. F., Monroe, J. G. (2006). Analysis of the Individual Contributions of Ig{alpha} (CD79a)- and Igbeta (CD79b)-Mediated Tonic Signaling for Bone Marrow B Cell Development and Peripheral B Cell Maturation. J. Immunol. 177: 7913-7922 [Abstract] [Full Text]  
• Dragone, L. L., Myers, M. D., White, C., Gadwal, S., Sosinowski, T., Gu, H., Weiss, A. (2006). Src-like adaptor protein (SLAP) regulates B cell receptor levels in a c-Cbl-dependent manner. Proc. Natl. Acad. Sci. USA 103: 18202-18207 [Abstract] [Full Text]  
• Gazumyan, A., Reichlin, A., Nussenzweig, M. C. (2006). Ig{beta} tyrosine residues contribute to the control of B cell receptor signaling by regulating receptor internalization. JEM 203: 1785-1794 [Abstract] [Full Text]  
• Hamerman, J. A., Lanier, L. L. (2006). Inhibition of Immune Responses by ITAM-Bearing Receptors. Sci Signal 2006: re1-re1 [Abstract] [Full Text]  
• Heltemes-Harris, L., Liu, X., Manser, T. (2005). An antibody VH gene that promotes marginal zone B cell development and heavy chain allelic inclusion. Int Immunol 17: 1447-1461 [Abstract] [Full Text]  
• Liu, X., Manser, T. (2005). Antinuclear Antigen B Cells That Down-Regulate Surface B Cell Receptor during Development to Mature, Follicular Phenotype Do Not Display Features of Anergy In Vitro. J. Immunol. 174: 4505-4515 [Abstract] [Full Text]  
• Pike, K. A., Ratcliffe, M. J. H. (2005). Dual Requirement for the Ig{alpha} Immunoreceptor Tyrosine-Based Activation Motif (ITAM) and a Conserved Non-Ig{alpha} ITAM Tyrosine in Supporting Ig{alpha}{beta}-Mediated B Cell Development. J. Immunol. 174: 2012-2020 [Abstract] [Full Text]  
• Edry, E., Melamed, D. (2004). Receptor Editing in Positive and Negative Selection of B Lymphopoiesis. J. Immunol. 173: 4265-4271 [Abstract] [Full Text]  
• Sato, H., Saito-Ohara, F., Inazawa, J., Kudo, A. (2004). Pax-5 Is Essential for {kappa} Sterile Transcription during Ig{kappa} Chain Gene Rearrangement. J. Immunol. 172: 4858-4865 [Abstract] [Full Text]  
• Reichlin, A., Gazumyan, A., Nagaoka, H., Kirsch, K. H., Kraus, M., Rajewsky, K., Nussenzweig, M. C. (2004). A B Cell Receptor with Two Ig{alpha} Cytoplasmic Domains Supports Development of Mature But Anergic B Cells. JEM 199: 855-865 [Abstract] [Full Text]  
• Pike, K. A., Iacampo, S., Friedmann, J. E., Ratcliffe, M. J. H. (2004). The Cytoplasmic Domain of Ig{alpha} Is Necessary and Sufficient to Support Efficient Early B Cell Development. J. Immunol. 172: 2210-2218 [Abstract] [Full Text]  
• Heltemes-Harris, L., Liu, X., Manser, T. (2004). Progressive Surface B Cell Antigen Receptor Down-Regulation Accompanies Efficient Development of Antinuclear Antigen B Cells to Mature, Follicular Phenotype. J. Immunol. 172: 823-833 [Abstract] [Full Text]  
• Tretter, T., Ross, A. E., Dordai, D. I., Desiderio, S. (2003). Mimicry of Pre-B Cell Receptor Signaling by Activation of the Tyrosine Kinase Blk. JEM 198: 1863-1873 [Abstract] [Full Text]  
• Gordon, M. S., Kanegai, C. M., Doerr, J. R., Wall, R. (2003). Somatic hypermutation of the B cell receptor genes B29 (Igbeta , CD79b) and mb1 (Igalpha , CD79a). Proc. Natl. Acad. Sci. USA 100: 4126-4131 [Abstract] [Full Text]  
• Pelanda, R., Braun, U., Hobeika, E., Nussenzweig, M. C., Reth, M. (2002). B Cell Progenitors Are Arrested in Maturation but Have Intact VDJ Recombination in the Absence of Ig-{alpha} and Ig-{beta}. J. Immunol. 169: 865-872 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS