Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease.
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.
Wang
Duncheng
D
Department of Biochemistry, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, USA.
John
Shinu A
SA
Clements
James L
JL
Percy
Dean H
DH
Barton
Kevin P
KP
Garrett-Sinha
Lee Ann
LA
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010950:Plasma Cells / Q000276:immunology* / Q000473:pathology; D050784:Proto-Oncogene Protein c-ets-1 / Q000172:deficiency* / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology*
C494042:Ets1 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9