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Pre-T cell receptor (TCR) and TCR-controlled checkpoints in T cell differentiation are set by Ikaros.

Winandy S, Wu L, Wang JH, Georgopoulos K - J. Exp. Med. (1999)

Bottom Line: T cell differentiation relies on pre-T cell receptor (TCR) and TCR signaling events that take place at successive steps of the pathway.Subsequent events in T cell development mediated by TCR involving transition from the double positive to the single positive stage are also regulated by Ikaros.We conclude that Ikaros regulates T cell differentiation, selection, and homeostasis by providing signaling thresholds for pre-TCR and TCR.

View Article: PubMed Central - PubMed

Affiliation: Cutaneous Biology Research Center, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.

ABSTRACT
T cell differentiation relies on pre-T cell receptor (TCR) and TCR signaling events that take place at successive steps of the pathway. Here, we show that two of these T cell differentiation checkpoints are regulated by Ikaros. In the absence of Ikaros, double negative thymocytes can differentiate to the double positive stage without expression of a pre-TCR complex. Subsequent events in T cell development mediated by TCR involving transition from the double positive to the single positive stage are also regulated by Ikaros. Nonetheless, in Ikaros-deficient thymocytes, the requirement of pre-TCR expression for expansion of immature thymocytes as they progress to the double positive stage is still maintained, and the T cell malignancies that invariably arise in the thymus of Ikaros-deficient mice are dependent on either pre-TCR or TCR signaling. We conclude that Ikaros regulates T cell differentiation, selection, and homeostasis by providing signaling thresholds for pre-TCR and TCR.

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Deregulated development of the TCR-γ/δ lineage in the absence of Ikaros. (A) Schematic depicting block in differentiation which occurs in TCR-β2/− thymocytes. (B) Representative FACS® profiles showing staining patterns of thymocytes in young TCR-β2/− mice with the following Ikaros (Ik) genotypes: +/+ and DN+/−. Thymocytes were stained with anti-CD4–PE, anti-CD8α–Cychrome, and anti–TCR-γδ–FITC. Numbers shown in FACS® profiles denote percentage of cells that fall into each quadrant. “Total thymocytes” shows profiles of total thymocyte populations, whereas “TCRγδ+” only shows profiles of cells that stain positively for TCR-γ/δ. (C) Numbers of double positive and double negative cells per thymus in 3–6-wk-old Ikaros (Ik) wild-type and DN+/− mice on the TCR-β2/− genetic background. Average number (AVG) of precursors (×10−4) that fall into each subset is shown at the top of the graph.
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Figure 5: Deregulated development of the TCR-γ/δ lineage in the absence of Ikaros. (A) Schematic depicting block in differentiation which occurs in TCR-β2/− thymocytes. (B) Representative FACS® profiles showing staining patterns of thymocytes in young TCR-β2/− mice with the following Ikaros (Ik) genotypes: +/+ and DN+/−. Thymocytes were stained with anti-CD4–PE, anti-CD8α–Cychrome, and anti–TCR-γδ–FITC. Numbers shown in FACS® profiles denote percentage of cells that fall into each quadrant. “Total thymocytes” shows profiles of total thymocyte populations, whereas “TCRγδ+” only shows profiles of cells that stain positively for TCR-γ/δ. (C) Numbers of double positive and double negative cells per thymus in 3–6-wk-old Ikaros (Ik) wild-type and DN+/− mice on the TCR-β2/− genetic background. Average number (AVG) of precursors (×10−4) that fall into each subset is shown at the top of the graph.

Mentions: We next examined the effects of the Ikaros mutation on differentiation of the γ/δ T cell lineage. Block in α/β T cell differentiation caused by lack of expression of the TCR β chain is observed at the late double negative precursor stage (stage C; Fig. 5 A). However, this differentiation block does not affect differentiation of thymocyte precursors along the γ/δ T cell pathway 4. Analysis of the role of Ikaros in TCR-γ/δ lineage differentiation and homeostasis was studied using the Ikaros DN+/− mutation, since only a very small subset of TCR-γ/δ lineages, those found in the mucosal epithelia, develops on the Ikaros −/− genetic background.


Pre-T cell receptor (TCR) and TCR-controlled checkpoints in T cell differentiation are set by Ikaros.

Winandy S, Wu L, Wang JH, Georgopoulos K - J. Exp. Med. (1999)

Deregulated development of the TCR-γ/δ lineage in the absence of Ikaros. (A) Schematic depicting block in differentiation which occurs in TCR-β2/− thymocytes. (B) Representative FACS® profiles showing staining patterns of thymocytes in young TCR-β2/− mice with the following Ikaros (Ik) genotypes: +/+ and DN+/−. Thymocytes were stained with anti-CD4–PE, anti-CD8α–Cychrome, and anti–TCR-γδ–FITC. Numbers shown in FACS® profiles denote percentage of cells that fall into each quadrant. “Total thymocytes” shows profiles of total thymocyte populations, whereas “TCRγδ+” only shows profiles of cells that stain positively for TCR-γ/δ. (C) Numbers of double positive and double negative cells per thymus in 3–6-wk-old Ikaros (Ik) wild-type and DN+/− mice on the TCR-β2/− genetic background. Average number (AVG) of precursors (×10−4) that fall into each subset is shown at the top of the graph.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2195663&req=5

Figure 5: Deregulated development of the TCR-γ/δ lineage in the absence of Ikaros. (A) Schematic depicting block in differentiation which occurs in TCR-β2/− thymocytes. (B) Representative FACS® profiles showing staining patterns of thymocytes in young TCR-β2/− mice with the following Ikaros (Ik) genotypes: +/+ and DN+/−. Thymocytes were stained with anti-CD4–PE, anti-CD8α–Cychrome, and anti–TCR-γδ–FITC. Numbers shown in FACS® profiles denote percentage of cells that fall into each quadrant. “Total thymocytes” shows profiles of total thymocyte populations, whereas “TCRγδ+” only shows profiles of cells that stain positively for TCR-γ/δ. (C) Numbers of double positive and double negative cells per thymus in 3–6-wk-old Ikaros (Ik) wild-type and DN+/− mice on the TCR-β2/− genetic background. Average number (AVG) of precursors (×10−4) that fall into each subset is shown at the top of the graph.
Mentions: We next examined the effects of the Ikaros mutation on differentiation of the γ/δ T cell lineage. Block in α/β T cell differentiation caused by lack of expression of the TCR β chain is observed at the late double negative precursor stage (stage C; Fig. 5 A). However, this differentiation block does not affect differentiation of thymocyte precursors along the γ/δ T cell pathway 4. Analysis of the role of Ikaros in TCR-γ/δ lineage differentiation and homeostasis was studied using the Ikaros DN+/− mutation, since only a very small subset of TCR-γ/δ lineages, those found in the mucosal epithelia, develops on the Ikaros −/− genetic background.

Bottom Line: T cell differentiation relies on pre-T cell receptor (TCR) and TCR signaling events that take place at successive steps of the pathway.Subsequent events in T cell development mediated by TCR involving transition from the double positive to the single positive stage are also regulated by Ikaros.We conclude that Ikaros regulates T cell differentiation, selection, and homeostasis by providing signaling thresholds for pre-TCR and TCR.

View Article: PubMed Central - PubMed

Affiliation: Cutaneous Biology Research Center, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.

ABSTRACT
T cell differentiation relies on pre-T cell receptor (TCR) and TCR signaling events that take place at successive steps of the pathway. Here, we show that two of these T cell differentiation checkpoints are regulated by Ikaros. In the absence of Ikaros, double negative thymocytes can differentiate to the double positive stage without expression of a pre-TCR complex. Subsequent events in T cell development mediated by TCR involving transition from the double positive to the single positive stage are also regulated by Ikaros. Nonetheless, in Ikaros-deficient thymocytes, the requirement of pre-TCR expression for expansion of immature thymocytes as they progress to the double positive stage is still maintained, and the T cell malignancies that invariably arise in the thymus of Ikaros-deficient mice are dependent on either pre-TCR or TCR signaling. We conclude that Ikaros regulates T cell differentiation, selection, and homeostasis by providing signaling thresholds for pre-TCR and TCR.

Show MeSH
Related in: MedlinePlus