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Discovery and Function of B-Cell IgD Low (BDL) B Cells in Immune Tolerance.
J Mol Biol. 2020 Jun 29 [Online ahead of print]JM

Abstract

It is now appreciated that in addition to their role in humoral immunity, B cells also exert regulatory mechanisms that lead to attenuation of inflammatory responses. The concept of B-cell regulation became well recognized when mice deficient in B cells due to genetic disruption were shown to be refractory to recovery from the signs of experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis. This seminal study spurred the search for B-cell regulatory phenotypes and mechanisms of action. Our approach was to utilize differential B-cell depletion with anti-CD20 to retain B cells whose presence were required to achieve EAE recovery. Utilizing flow cytometry, adoptive cell therapy and genetic approaches, we discovered a new B-cell subset that, upon adoptive transfer into B cell-deficient mice, was sufficient to promote EAE recovery. This B-cell subset is IgM+, but due to low/negative IgD cell surface expression, it was named B-cell IgD low (BDL). Mechanistically, we found that in the absence of BDL, the absolute cell number of CD4+Foxp3+ T regulatory cells (Treg), essential for immune tolerance, was significantly reduced. Furthermore, we found that BDL expression of glucocorticoid-induced tumor necrosis factor ligand (GITRL) was essential for induction of Treg proliferation and maintenance of their homeostasis. Thus, we have identified a new B-cell subset that is critical for immunological tolerance through interactions with Treg.

Authors+Show Affiliations

Versiti Blood Research Institute, Milwaukee, WI, USA; Molecular Biology Department, National Research Centre, El-Buhouth St., Doki, Cairo, Egypt.Versiti Blood Research Institute, Milwaukee, WI, USA.Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, USA.Versiti Blood Research Institute, Milwaukee, WI, USA; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA.Versiti Blood Research Institute, Milwaukee, WI, USA; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: bdittel@versiti.org.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

32615130

Citation

Khalil, Mohamed I., et al. "Discovery and Function of B-Cell IgD Low (BDL) B Cells in Immune Tolerance." Journal of Molecular Biology, 2020.
Khalil MI, Gurski CJ, Dittel LJ, et al. Discovery and Function of B-Cell IgD Low (BDL) B Cells in Immune Tolerance. J Mol Biol. 2020.
Khalil, M. I., Gurski, C. J., Dittel, L. J., Neu, S. D., & Dittel, B. N. (2020). Discovery and Function of B-Cell IgD Low (BDL) B Cells in Immune Tolerance. Journal of Molecular Biology. https://doi.org/10.1016/j.jmb.2020.06.023
Khalil MI, et al. Discovery and Function of B-Cell IgD Low (BDL) B Cells in Immune Tolerance. J Mol Biol. 2020 Jun 29; PubMed PMID: 32615130.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery and Function of B-Cell IgD Low (BDL) B Cells in Immune Tolerance. AU - Khalil,Mohamed I, AU - Gurski,Cody J, AU - Dittel,Landon J, AU - Neu,Savannah D, AU - Dittel,Bonnie N, Y1 - 2020/06/29/ PY - 2020/05/11/received PY - 2020/06/16/revised PY - 2020/06/23/accepted PY - 2020/7/3/pubmed PY - 2020/7/3/medline PY - 2020/7/3/entrez KW - B-cell IgD low KW - CD4(+)Foxp3(+) T regulatory cell KW - experimental autoimmune encephalomyelitis KW - glucocorticoid-induced tumor necrosis factor ligand KW - immune tolerance JF - Journal of molecular biology JO - J. Mol. Biol. N2 - It is now appreciated that in addition to their role in humoral immunity, B cells also exert regulatory mechanisms that lead to attenuation of inflammatory responses. The concept of B-cell regulation became well recognized when mice deficient in B cells due to genetic disruption were shown to be refractory to recovery from the signs of experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis. This seminal study spurred the search for B-cell regulatory phenotypes and mechanisms of action. Our approach was to utilize differential B-cell depletion with anti-CD20 to retain B cells whose presence were required to achieve EAE recovery. Utilizing flow cytometry, adoptive cell therapy and genetic approaches, we discovered a new B-cell subset that, upon adoptive transfer into B cell-deficient mice, was sufficient to promote EAE recovery. This B-cell subset is IgM+, but due to low/negative IgD cell surface expression, it was named B-cell IgD low (BDL). Mechanistically, we found that in the absence of BDL, the absolute cell number of CD4+Foxp3+ T regulatory cells (Treg), essential for immune tolerance, was significantly reduced. Furthermore, we found that BDL expression of glucocorticoid-induced tumor necrosis factor ligand (GITRL) was essential for induction of Treg proliferation and maintenance of their homeostasis. Thus, we have identified a new B-cell subset that is critical for immunological tolerance through interactions with Treg. SN - 1089-8638 UR - https://www.unboundmedicine.com/medline/citation/32615130/Discovery_and_Function_of_B_Cell_IgD_Low_(BDL)_B_Cells_in_Immune_Tolerance L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-2836(20)30428-9 DB - PRIME DP - Unbound Medicine ER -
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