Prostaglandin E2-dependent induction of B cell unresponsiveness. Role of surface Ig and Fc receptors.
Previously, we demonstrated that two signals were required for accessory cells to induce B cell unresponsiveness: tolerogenic Ig and PG. The purpose of this study was to investigate whether PGE2, in an accessory cellfree system, promoted fluorescein-specific B cell unresponsiveness in conjunction with ligands which bound to surface Ig (sIg) and/or FcR. Several conditions were found whereby PGE2 was obligatory for unresponsiveness. In the presence of aggregated, but not monomeric non-Ig fluorescein-Ag, direct plaque-forming cell responses were reduced by 60%. In contrast, engagement of the B cell FcR by aggregated IgG2b or by the 2.4G2 anti-FcR mAb failed to induce unresponsiveness, even when PGE2 was present. These data suggested that PGE2 could promote sIg-mediated negative signaling. A second condition where PGE2 promoted unresponsiveness occurred when sIg and FcR were simultaneously engaged by monomeric ligands. However, when sIg and FcR were cross-linked, PGE2-independent B cell unresponsiveness occurred. Interestingly, when subinhibitory doses of cross-linking agents were used, PGE2 dependent negative signaling resulted. PGE2 can thereby promote B cell unresponsiveness in three different situations. First, when sIg is extensively cross-linked by aggregated antigens or those with repeating determinants. Second, when sIg is engaged by monomeric antigen and when the B cell FcR is also occupied. Third, under conditions where B cell sIg and FcR are inadequately cross-linked. These situations can occur in vivo when macrophages in the B cell microenvironment (i.e., follicles) secrete PGE2 and when Ag with repeating epitopes, or immune complexes capable of binding B cell sIg and FcR are present. Thus, PGE2 can serve as an important regulatory element in limiting antibody formation.
Schad
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Cancer Center, University of Rochester School of Medicine and Dentistry, NY 14642.
Phipps
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RP
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D002003:Brucella abortus / Q000276:immunology; D003432:Cross-Linking Reagents; D015232:Dinoprostone / Q000502:physiology*; D005452:Fluoresceins; D006241:Haptens / Q000276:immunology; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D011961:Receptors, Fc / Q000502:physiology*; D015398:Signal Transduction
D003432:Cross-Linking Reagents; D005452:Fluoresceins; D006241:Haptens; D046911:Macromolecular Substances; D011947:Receptors, Antigen, B-Cell; D011961:Receptors, Fc; D015232:Dinoprostone