Impaired Generation of CD8+ Thymocytes in Ets-1-Deficient Mice

Abstract

The Ets family of transcription factors function as key regulators of multiple aspects of immune cell development and function. To date, Ets-1 has been implicated in regulating early stages of thymic maturation and lymphocyte function and homeostasis. This report describes a novel role for Ets-1 in supporting later stages of thymic selection, in that positive selection of MHC class I-restricted CD4+CD8+ double-positive thymocytes is markedly inhibited in mice expressing a hypomorphic allele of Ets-1. This effect is thymocyte intrinsic, as Ets-1 mutant thymocytes fail to efficiently generate CD8+ single-positive thymocytes in mixed bone marrow chimeric backgrounds. Although peripheral CD8+ T cells are present in Ets-1 mutant mice, both CD4+ and CD8+ subsets contain an elevated proportion of cells with an effector memory (CD62L−CD44+) phenotype. In addition, while thymic expression of Thy1 is relatively normal, peripheral T cells isolated from Ets-1 mutant mice display a striking loss of Thy1 expression. These data identify Ets-1 as a key transcription factor regulating thymocyte positive selection and lineage commitment of MHC class I-restricted thymocytes.

Ets1 is required for proper migration and differentiation of the cardiac neural crest

“…Ets1-deficient mice have been previously generated and have defects in natural killer (NK) cell, Tcell, and B-cell development, as well as in vascular inflammation and remodeling (Barton et al, 1998;Bories et al, 1995;Clements et al, 2006;Eyquem et al, 2004a;Eyquem et al, 2004b;Wang et al, 2005;Zhan et al, 2005). In addition, a p51-isoform specific disruption of the murine Ets1 gene has also been generated and found to cause defects in lymphoid maturation (Higuchi et al, 2007).…”

Ets-1 Regulates Plasma Cell Differentiation by Interfering with the Activity of the Transcription Factor Blimp-1

“…The transcription factors Bcl-6 and Bach-2 are known to repress Blimp-1 expression in cells committed to a germinal center fate (16,17). In addition, the transcription factor Pax-5 can repress Blimp-1 expression in mature B cells, although it is not clear whether this is due to direct binding to the Blimp-1 gene or via up-regulation of Bcl-6 (18,19). Evidence also suggests that the transcription factor Ets-1 may play a key role in regulating Blimp-1 activity, since mice lacking Ets-1 exhibit a strikingly increased number of IgM-secreting plasma cells in their lymphoid organs (20,21).…”

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).…”

“…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). The mammalian Ets1 gene produces two major protein isoforms, full-length p51-Ets1 and p42-Ets1, which arise from alternative splicing of exon VII of Ets1 hnRNA with no disruption in the reading frame (5,24,29).…”