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Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado 80206; the Department of Immunology, University of Colorado Health Science Center, Denver, Colorado 80220; || EISAI London Research Laboratories, University College of London, London WC1E 6BT; the ¶ Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; and the ** Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706
The B cell receptor (BCR) triggers a variety of biological responses that differ depending upon the properties of the antigen. A panel of M13 phage-displayed peptide ligands with varying affinity for the 3-83 antibody was generated to explore the role of antigen-BCR affinity in cell activation studies using primary 3-83 transgenic mouse B cells. Multiple parameters of activation were measured. T cell–independent B cell proliferation, antibody secretion, induction of germline immunoglobulin
1 transcripts, and B cell production of interleukin (IL) 2 and interferon responses were better correlated with antigen-BCR affinity than with receptor occupancy. In contrast, other responses, such as upregulation of major histocompatibility complex class II and B7.2 (CD86), secretion of IL-6, and B cell proliferation in the context of CD40 signaling were only weakly dependent on antigen affinity. Biochemical analysis revealed that at saturating ligand concentrations the ability of phage to stimulate some early signaling responses, such as Ca++ mobilization and tyrosine phosphorylation of syk or Ig
, was highly affinity dependent, whereas the ability to stimulate Lyn phosphorylation was less so. These data suggest that the BCR is capable of differential signaling. The possibility that differential BCR signaling by antigen determines whether an antibody response will be T independent or dependent is discussed.
Key Words: B lymphocytes • differential activation • phage library • immunoglobulin • transgenic mice
Abbreviations used: BCR, B cell receptor; ITAM, immunotyrosine-based motifs; PVDF, polyvinylidene difluoride; trp, tryptophan.
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