B cell tolerance induction by cross-linking of membrane IgM, but not IgD, and synergy by cross-linking of both isotypes

Arti Gaur, Xiao Rui Yao, David W. Scott*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Previous studies in our laboratory demonstrated that overnight exposure of adult splenic B cells to anti-Ig resulted in an unresponsive state characterized by decreased antibody synthesis but normal mitogen-driven proliferation (i.e., anergy). Because both anti-F(ab′)2 and anti-μ were equally effective at inducing tolerance, it was important to determine whether cross-linking of IgD together with or separately from IgM influenced the induction of unresponsiveness. Although anti-μ induced significant unresponsiveness, treatment of adult splenic B cells with anti-δ alone generally failed to reduce the subsequent response to either LPS or fluoresceinated Brucella abortus. Interestingly, anti-δ synergized with suboptimal concentrations of anti-μ to induce tolerance. Synergy could be observed in this system when anti-δ was added either simultaneously with or before (but not after) anti-μ; moreover, anti-δ was effective in a pretreatment (wash-out) protocol. To investigate the role of protein tyrosine kinase (PTK) activity in tolerance induction, splenic B cells were treated with tyrphostin before treatment with either anti-μ or anti-δ. We found that pretreatment with tyrphostin for 2 h before the addition of anti-μ prevented the induction of unresponsiveness with this antibody, whereas this PTK inhibitor facilitated tolerance when used with anti-δ treatment only. We propose that cross-linking of surface IgM directly or indirectly invokes a tyrphostin-sensitive, PTK-dependent pathway leading to the early events in tolerance induction, which can be augmented under limiting conditions by anti-IgD. Because cross-linking of either receptor initiates several common pathways, simultaneous cross-linking can lead to synergy and a dominance of the IgM signal. In contrast, IgD alone may fail to elicit tolerance because this isotype may also be associated with different PTK that cause positive signaling.

Original languageEnglish
Pages (from-to)1663-1669
Number of pages7
JournalJournal of Immunology
Issue number5
StatePublished - 1993
Externally publishedYes


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