Regulation of B-cell tolerance and triggering by macrophages and lymphoid dendritic cells.
This review explores the concept that accessory cells differentially regulate immune responses such that tolerance or immunity is induced. Macrophages and lymphoid dendritic cells differentially present hapten-conjugated Ig, antigen-antibody complexes and hapten-modified self such that hapten-specific B-cell development into IgM-secreting cells is blocked or stimulated. The mechanism by which macrophages inhibit B-lymphocyte differentiation is dependent upon an antigen-specific signal and a second nonspecific signal supplied by macrophage-derived E-series PG. In contrast, non PGE-producing lymphoid dendritic cells promoted maturation to IgM PFC by acting as a powerful stimulator of T-lymphocyte IL-2 production. PGE2, but not the structurally similar compound PGF2 alpha, synergized with ligands (e.g. antigen-antibody complexes) which cross-link B-cell sIg or both sIg and Fc receptors to promote hapten-specific unresponsiveness to thymus-independent antigens. Murine B lymphomas were also tested for sensitivity to E- and F-series PG. These cells varied in sensitivity to PGE2 and PGE1 in terms of growth inhibition, suggesting heterogeneity in B-cell PG responsiveness. Interestingly, E-series PG synergized with anti-Ig reagents to kill B lymphomas representative of "immature" normal B cells. In contrast to the effects of PGE on IgM production, we discovered that E-, but not F-series, PG promoted B-cell isotype switching to IgE and IgG1 in the presence of IL-4 and the polyclonal B-cell activator LPS. Other agents which stimulate a cAMP response also promoted isotype switching. These observations indicate that PGE are not obligatory inhibitors of immune responses. Research is in progress to uncover the molecular mechanisms by which PGE are "positive" or "negative" regulators of B lymphocytes.
Phipps
R P
RP
Immunology Division, Cancer Center, University of Rochester, School of Medicine, New York 14642.
Roper
R L
RL
Stein
S H
SH
D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D007132:Immunoglobulin Isotypes / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D011458:Prostaglandins E / Q000502:physiology; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D000936:Antigen-Antibody Complex; D007132:Immunoglobulin Isotypes; D011458:Prostaglandins E