International Immunology Advance Access originally published online on July 28, 2005
International Immunology 2005 17(9):1179-1191; doi:10.1093/intimm/dxh295
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Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease
1 Department of Biochemistry, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, USA
2 Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
3 Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G 2W1
4 Department of Medicine, Section of Hematology/Oncology, Loyola University, Chicago, IL 60611, USA
Correspondence to: L. A. Garrett-Sinha; E-mail: leesinha{at}buffalo.edu
It has been shown that mice with a targeted mutation in the Ets-1 gene exhibit increased B cell terminal differentiation to IgM-secreting plasma cells. Here, we show that mice, formerly described to lack Ets-1 protein, actually express low levels of an internally deleted Ets-1 protein. Mice harboring this Ets-1 hypomorphic allele possess very few marginal zone B cells and have increased expression of activation markers on follicular B cells. Adoptive transfer experiments indicate that this activated phenotype can be reversed upon transfer of Ets-1-deficient B cells to a wild-type host, suggesting a role for B cell-extrinsic factors in regulating the activated state. Supporting this observation, the reverse transfer experiment of wild-type B cells into an Ets-1-deficient host resulted in increased expression of activation markers on the transferred B cells. However, there are also cell-intrinsic changes in Ets-1-deficient B cells as demonstrated by their increased differentiation to plasma cells in vitro in response to stimulation with cytosine-phosphate-guanine DNA sequence-containing oligodeoxynucleotide [CpG DNA, a Toll-like receptor (TLR) 9 ligand]. Consistent with the activated phenotype and increased terminal differentiation of Ets-1-deficient B cells, Ets-1 mutant mice develop autoimmune disease. Hence, our studies establish Ets-1 as an important regulator of peripheral B cell differentiation and B cell responses to TLR9 activation.
Keywords: B cell activation, CpG oligodeoxynucleotide, marginal zone, Pointed domain
* Both authors contributed equally to these studies.
Transmitting editor: P. Ohashi
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