Project I: Recent in vitro studies have established that activated B cells express OX40 ligand (L) and become stimulated to proliferate and secrete immunoglobulin (Ig) after crosslinking of OX40L by its counterreceptor OX40, which is expressed on activated T cells. In the present study we investigated the in vivo role of this receptor-ligand pair for the interaction of T and B cells in the course of the T-dependent B cells response against 2,4,6-trinitrophenyl-keyhole limpet hemocyanin. We demonstrated that blocking of OX40-OX40L interaction with a polyclonal anti-OX40 antibody resulted in a profound decrease of the anti-hapten IgG responses, whereas the anti-hapten IgM responses were grossly unchanged. In addition, we showed that this antibody treatment leads to an inhibition of the development of PALS-associated B cell foci, whereas the formation of germinal centers remained intact. We conclude from these data that the OX40-OX40L interaction in vivo is necessary to the differentiation of activated B cells into highly Ig-producing cells. Project II: In these studies, we compared the activation requirements of sIgM+/sIgD+ B cells with those of isotype-switched sIgM-/sIgA+ B cells. We found that whereas sIgM+ B cells respond to TI and TD Ags with no significant bias toward one or the other stimulus, sIgA+ B cells were deficient in their ability to respond to Ag-receptor crosslinking but responded remarkably well to TD stimuli. Thus, anti-IgA-dextran, anti-kappa-dextran, or various immobilized anti-IgA Abs induced only low-level IgA B cell proliferation and no IgA secretion in the presence of various lymphokines; in marked contrast, sIgA+ B cells responded to cognate T cell stimulation as well as to stimulation by CD40L-bearing fibroblasts by secreting large amounts of IgA (up to 240,000 ng/ml/105 cells). In confirmation of these results, whole Peyer~s patch (PP) or lamina propria (LP) populations containing less than 15% sIgA+ B cells stimulated with a noncognate T cell stimulus of T cell membrane secreted mainly IgA (68%-94% of the total Ig secreted) and relatively little IgM. In further studies, we analyzed the role of Ig receptor crosslinking in T cell dependent stimulation of both sIgM+/sIgD+ B cells and sIgA+ B cells. We demonstrate that purified sIgA+ B cells pretreated with anti-IgA-dextran with higher doses (1 and 10 microgram/ml of antibody) led to a profound suppression of IgA secretion (greater than 90%). In contrast, sIgM+/sIgD+ B cells pretreated with anti-IgD-dextran or with anti-IgM-dextran did not show significant inhibition. Finally, we showed that anti-IgA-dextran-mediated suppression could be reversed by stimulation of sIgA+ B cells with fibroblasts expressing CD40L. These studies imply that Ig receptor crosslinking renders postswitch sIgA B cells unresponsive to subsequent stimulation via activated T cells but that this unresponsiveness is overcome by a persistent CD40Lhigh signal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000356-14
Application #
2566757
Study Section
Special Emphasis Panel (LCI)
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
1996
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
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