All-or-none suppression of B cell terminal differentiation by environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Many environmental contaminants can disrupt the adaptive immune response. Exposure to the ubiquitous aryl hydrocarbon receptor (AhR) ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other agonists suppresses the antibody response. The underlying pathway mechanism by which TCDD alters B cell function is not well understood. The present study investigated the mechanism of AhR-mediated pathways and mode of suppression by which TCDD perturbs terminal differentiation of B cells to plasma cells and thereby impairs antibody production. An integrated approach combining computational pathway modeling and in vitro assays with primary mouse B cells activated by lipopolysaccharide was employed. We demonstrated that suppression of the IgM response by TCDD occurs in an all-or-none (binary) rather than graded mode: i.e., it reduces the number of IgM-secreting cells in a concentration-dependent manner without affecting the IgM content in individual plasma cells. The mathematical model of the gene regulatory circuit underpinning B cell differentiation revealed that two previously identified AhR-regulated pathways, inhibition of signaling protein AP-1 and activation of transcription factor Bach2, could account for the all-or-none mode of suppression. Both pathways disrupt the operation of a bistable-switch circuit that contains transcription factors Bcl6, Prdm1, Pax5, and Bach2 and regulates B cell fate. The model further predicted that by transcriptionally activating Bach2, TCDD might delay B cell differentiation and increase the likelihood of isotype switching, thereby altering the antibody repertoire. In conclusion, the present study revealed the mode and specific pathway mechanisms by which the environmental immunosuppressant TCDD suppresses B cell differentiation.
Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, NC 27709, USA. qzhang@thehamner.org
Qiang
Q
Zhang
Douglas E
DE
Kline
Sudin
S
Bhattacharya
Robert B
RB
Crawford
Rory B
RB
Conolly
Russell S
RS
Thomas
Melvin E
ME
Andersen
Norbert E
NE
Kaminski
D056704:Adaptive Immunity / Q000187:drug effects / Q000276:immunology; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D050976:Basic-Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D003198:Computer Simulation; D005260:Female; D005434:Flow Cytometry; D007075:Immunoglobulin M / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011897:Random Allocation; D018336:Receptors, Aryl Hydrocarbon / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000276:immunology
C102109:Bach2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D007075:Immunoglobulin M; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D018808:Transcription Factor AP-1