The Journal of Experimental Medicine
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Published online 20 August 2001. doi:10.1084/jem.194.4.455
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© The Rockefeller University Press, 0022-1007/2001/8/455/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 4, August 20, 2001 455-470

Original Article

Interference with Immunoglobulin (Ig){alpha} Immunoreceptor Tyrosine–Based Activation Motif (Itam) Phosphorylation Modulates or Blocks B Cell Development, Depending on the Availability of an Igβ Cytoplasmic Tail

Manfred Krausa, Lily I. Paoa, Amy Reichlinb, Yun Hub, Beth Canonoc, John C. Cambierc, Michel C. Nussenzweigb, and Klaus Rajewskya

a Institute for Genetics, University of Cologne, D-50931 Cologne, Germany
b Laboratory of Molecular Immunology, The Rockefeller University and the Howard Hughes Medical Institute, New York, NY 10021
c Integrated Department of Immunology, University of Colorado Health Sciences Center and National Jewish Medical and Research Center, Denver, CO 80206
Harvard Medical School, 200 Longwood Ave., Boston, MA 02115.617-278-3131617-278-3274

kraus{at}cbr.med.harvard.edu

To determine the function of immunoglobulin (Ig){alpha} immunoreceptor tyrosine–based activation motif (ITAM) phosphorylation, we generated mice in which Ig{alpha} ITAM tyrosines were replaced by phenylalanines (Ig{alpha}FF/FF). Ig{alpha}FF/FFmice had a specific reduction of B1 and marginal zone B cells, whereas B2 cell development appeared to be normal, except that {lambda}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{alpha} non-ITAM tyrosines. Strikingly, when the Ig{alpha} ITAM mutation was combined with a truncation of Igβ, 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

K. Rajewsky's present address is Center for Blood Research, Harvard Medical School, 200 Longwood Ave., Boston, MA 02115.

Abbreviations used in this paper: BCR, B cell receptor; BM, bone marrow; ES, embryonic stem; ITAM, immunoreceptor tyrosine–based activation motif; MZ, marginal zone; PTK, protein tyrosine kinase; RT, room temperature; SH2, Src homology 2; TD, T cell–dependent; TI, T cell–independent.

© 2001 The Rockefeller University Press


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