Cell-autonomous requirement for TCF1 and LEF1 in the development of Natural Killer T cells

Berga-Bolaños, Rosa; Zhu, Wandi S.; Steinke, Farrah C.; Xue, Hai-Hui; Sen, Jyoti Misra

doi:10.1016/j.molimm.2015.09.017

Cited by 27 publications

(30 citation statements)

References 20 publications

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“…A role for TCF-1 in the differentiation of NKT cells has also been established. Mice deficient in TCF-1 or with a conditional knockout in CD4 + cells displayed reduced numbers of NKT cells in the thymus and periphery [152,153]. Additional deletion of LEF-1 in the TCF-1 conditional knockout mice further diminished NKT cell numbers.…”

Section: Nkt Cellsmentioning

confidence: 97%

“…Additional deletion of LEF-1 in the TCF-1 conditional knockout mice further diminished NKT cell numbers. Thymocyte-and T cell-specific deletion of b-catenin in mice selectively diminished the differentiation of NKT2 and NKT17 cells, but not NKT1 cells, resulting in fewer IL-4 + NKT cells upon stimulation in vivo and in vitro [152,154]. The direct involvement of WNT signaling in these processes remains to be established.…”

Section: Nkt Cellsmentioning

confidence: 99%

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Roles of WNT, NOTCH, and Hedgehog signaling in the differentiation and function of innate and innate-like lymphocytes

Kling

Blumenthal

2016

Journal of Leukocyte Biology

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Innate lymphoid cells (ILCs) and innate-like lymphocytes have important roles in immune responses in the context of infection, cancer, and autoimmunity. The factors involved in driving the differentiation and function of these cell types remain to be clearly defined. There are several cellular signaling pathways involved in embryogenesis, which continue to function in adult tissue. In particular, the WNT, NOTCH, and Hedgehog signaling pathways are emerging as regulators of hematopoietic cell development and differentiation. This review discusses the currently known roles of WNT, NOTCH, and Hedgehog signaling in the differentiation and function of ILCs and innate-like lymphocytes.

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Section: Nkt Cellsmentioning

confidence: 97%

Section: Nkt Cellsmentioning

confidence: 99%

Roles of WNT, NOTCH, and Hedgehog signaling in the differentiation and function of innate and innate-like lymphocytes

Kling

Blumenthal

2016

Journal of Leukocyte Biology

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“…The transcription factor Bcl11b is important for restraining the NKT17 differentiation program to allow for differentiation of iNKT2 and iNKT1 cells 27 . The transcription factor Lef1 is also important for iNKT cell proliferation and is crucial for differentiation of iNKT2 cells 28 , 29 . Loss of Lef1 leads to an increased proportion and function of iNKT17 cells suggesting Lef1 may restrain iNKT17 differentiation to promote iNKT2 differentiation.…”

Section: Introductionmentioning

confidence: 99%

The differentiation of ROR-γt expressing iNKT17 cells is orchestrated by Runx1

Thapa

Manso

Chung

et al. 2017

Sci Rep

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iNKT cells are a unique lineage of T cells that recognize glycolipid presented by CD1d. In the thymus, they differentiate into iNKT1, iNKT2 and iNKT17 effector subsets, characterized by preferential expression of Tbet, Gata3 and ROR-γt and production of IFN-γ, IL-4 and IL-17, respectively. We demonstrate that the transcriptional regulator Runx1 is essential for the generation of ROR-γt expressing iNKT17 cells. PLZF-cre Runx1 cKO mice lack iNKT17 cells in the thymus, spleen and liver. Runx1-deficient iNKT cells have altered expression of several genes important for iNKT17 differentiation, including decreased expression of IL-7Rα, BATF and c-Maf and increased expression of Bcl11b and Lef1. However, reduction of Lef1 expression or introduction of an IL-7Rα transgene is not sufficient to correct the defect in iNKT17 differentiation, demonstrating that Runx1 is a key regulator of several genes required for iNKT17 differentiation. Loss of Runx1 leads to a severe decrease in iNKT cell numbers in the thymus, spleen and liver. The decrease in cell number is due to a combined decrease in proliferation at Stage 1 during thymic development and increased apoptosis. Thus, we describe a novel role of Runx1 in iNKT cell development and differentiation, particularly in orchestrating iNKT17 differentiation.

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“…Pathway analysis confirmed significant upregulation of genes related to iNKT differentiation and effector function (Figure S1A in Supplementary Material; Figure 1 C). Genes essential for iNKT development and function, such as Tcf7, Sox4 , and Gzma , were highly upregulated in iNKT cells deficient in Id proteins ( 21 , 22 ). A subset of genes upregulated in L-DKO iNKT cells were also upregulated in L-DKO DP cells compared to WT DP cells (Figure 1 C).…”

Section: Resultsmentioning

confidence: 99%

Id Proteins Suppress E2A-Driven Invariant Natural Killer T Cell Development prior to TCR Selection

et al. 2018

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A family of transcription factors known as E proteins, and their antagonists, Id proteins, regulate T cell differentiation at critical developmental checkpoints. Id proteins promote the differentiation of conventional αβ T cells and suppress the expansion of innate-like αβ T cells known as invariant natural killer T (iNKT) cells. However, it remains to be determined whether Id proteins differentially regulate these distinct lineage choices in early stages of T cell development. In this manuscript, we report that in Id-deficient mice, uninhibited activity of the E protein family member E2A mediates activation of genes that support iNKT cell development and function. There is also biased rearrangement in Id-deficient DP cells that promotes selection into the iNKT lineage in these mice. The observed expansion of iNKT cells is not abrogated by blocking pre-TCR signaling, which is required for conventional αβ T cell development. Finally, E2A is found to be a key transcriptional regulator of both iNKT and γδNKT lineages, which appear to have shared lineage history. Therefore, our study reveals a previously unappreciated role of E2A in coordinating the development of the iNKT lineage at an early stage, prior to their TCR-mediated selection alongside conventional αβ T cells.

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Cell-autonomous requirement for TCF1 and LEF1 in the development of Natural Killer T cells

Cited by 27 publications

References 20 publications

Roles of WNT, NOTCH, and Hedgehog signaling in the differentiation and function of innate and innate-like lymphocytes

Roles of WNT, NOTCH, and Hedgehog signaling in the differentiation and function of innate and innate-like lymphocytes

The differentiation of ROR-γt expressing iNKT17 cells is orchestrated by Runx1

Id Proteins Suppress E2A-Driven Invariant Natural Killer T Cell Development prior to TCR Selection

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