Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease

Abstract

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.

Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma

“…The region contains 2 ETS transcription factors, ETS1 and FLI1. Known to be involved in the pathogenesis of multiple human cancers, 12,13 both ETS1 and FLI1 have an important role in the development of lymphoid tissues and immune system control, [14][15][16] regulating the activity of important players in B-cell growth and maturation such as the B-cell-specific activator protein PAX5 17,18 and the master regulator of plasma cell differentiation, PRDM1. 19 Notably, Ets1 and Fli1 are repressed during the late phases of B-cell differentiation in an in vitro murine system.…”

Regulation of Follicular B Cell Differentiation by the Related E26 Transformation-Specific Transcription Factors PU.1, Spi-B, and Spi-C

“…For flow cytometry, mouse splenocytes were washed after hypotonic lysis with ammonium chloride solution and stained with allophycocyanin-conjugated anti-B220 (RA3-6B2), PE-conjugated anti-CD19 (1D3), PE-Cy5-conjugated anti-IgM (II/41), PE-conjugated anti-CD93 (AA4.1), FITC-conjugated anti-IgD (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26), FITC-conjugated anti-CD23 (B3B4), FITC-conjugated anti-CD21 (eBio8D9), FITC-conjugated anti-CD1d (1B1), or biotin-conjugated anti-IL-21R (eBio4A9). All Abs were purchased from eBioscience (San Diego, CA).…”

“…However, few transcriptional regulators of the FO versus MZ cell fate decision have been identified. MZ B cell development is impaired in the absence of Notch2 signaling (12,13) as well as by mutation of the E26 transformation-specific (Ets) transcription factor Ets-1 (14). FO B cell development is moderately impaired in the absence of the Ets transcription factor Fli-1 (15).…”

Thymomegaly, Microsplenia, and Defective Homeostatic Proliferation of Peripheral Lymphocytes in p51-Ets1 Isoform-Specific Null Mice

“…These defects include reduced numbers of thymocytes, lymphoid cells in the spleen, and NK and NKT cells; loss of detectable NK and NKT cell activity; decreased proliferation and elevated apoptosis in mature T cells (4,6,40,58); increased differentiation of B cells to plasma cells with elevated serum immunoglobulin M; B-cell receptor signaling defects (12); abnormalities in T-cell receptor (TCR) ␤-selection in thymopoiesis; and an ineffective Th1 response (11,19). Complicating the assessment of Ets1 function is the fact that Ets1-null mice have been studied not only on a mixed genetic background (C57BL/6 ϫ 129Sv) predisposed to autoimmunity (53) but also with a line of Ets1-null mice that expresses a very low level of a neomorphic protein (ϳ1 to 5%) lacking the pointed domain of Ets1 (7,59). These Ets1-null mice present with a deficiency in CD8 ϩ thymocyte development and an elevated proportion of single-positive effector memory (CD62L Ϫ CD44 ϩ ) cells in both CD4 ϩ and CD8 ϩ peripheral T-cell populations (7).…”