The Multifaceted Roles of Bcl11b in Thymic and Peripheral T Cells: Impact on Immune Diseases

Avram, Dorina; Califano, Danielle

doi:10.4049/jimmunol.1400930

Cited by 88 publications

(89 citation statements)

References 62 publications

(142 reference statements)

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“…2A) (1), but the exact role of Bcl11b in this process depends on the unique regulatory context, which is not duplicated in any of the later T-cell contexts where Bcl11b works (reviewed in ref. 10) nor in type 2 ILC, where it also has a role (11,32,33). Until commitment (Fig.…”

Section: T-cell Specification Grn Transitions At Commitment: a Distinctmentioning

confidence: 99%

Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

Longabaugh

Zeng

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

148

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T-cell development from hematopoietic progenitors depends on multiple transcription factors, mobilized and modulated by intrathymic Notch signaling. Key aspects of T-cell specification network architecture have been illuminated through recent reports defining roles of transcription factors PU.1, GATA-3, and E2A, their interactions with Notch signaling, and roles of Runx1, TCF-1, and Hes1, providing bases for a comprehensively updated model of the T-cell specification gene regulatory network presented herein. However, the role of lineage commitment factor Bcl11b has been unclear. We use self-organizing maps on 63 RNA-seq datasets from normal and perturbed T-cell development to identify functional targets of Bcl11b during commitment and relate them to other regulomes. We show that both activation and repression target genes can be bound by Bcl11b in vivo, and that Bcl11b effects overlap with E2A-dependent effects. The newly clarified role of Bcl11b distinguishes discrete components of commitment, resolving how innate lymphoid, myeloid, and dendritic, and B-cell fate alternatives are excluded by different mechanisms.

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Section: T-cell Specification Grn Transitions At Commitment: a Distinctmentioning

confidence: 99%

Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

Longabaugh

Zeng

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

148

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“…Besides its expression in the central nervous system (CNS), BCL11B was shown to be widely expressed in all T-cell subsets, starting from the double-negative stage 2 (DN2 stage) and to be involved in various aspects of development, function, and survival of T cells (4). Indeed, BCL11B is a focal point essential for several checkpoints involved in T-cell commitment in early progenitors, selection at the DN2 stage, and differentiation of peripheral T cells (5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

“…BCL11B represses transcription of its target genes through interaction with several chromatin remodelling complexes and notably recruits NuRD complexes (nuclear remodeling and deacetylation complexes) via interaction with MTA1 and MTA2 (4,11,(16)(17)(18). Although originally characterized as a sequence-specific transcriptional repressor, BCL11B also behaves as a context-dependent transcriptional activator of the IL-2 and Cot kinase genes in CD4 ϩ T-cell activation (19,20).…”

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confidence: 99%

Protein Kinase C-Mediated Phosphorylation of BCL11B at Serine 2 Negatively Regulates Its Interaction with NuRD Complexes during CD4⁺ T-Cell Activation

Dubuissez

Loison

Paget

et al. 2016

Molecular and Cellular Biology

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Posttranslational modifications (PTMs) of transcription regulatory proteins allow the integration of various signaling and environmental cues into highly dynamic and controlled responses, thereby achieving coordinated gene expression programs essential for cell proliferation or differentiation.The transcription factor BCL11B/CTIP2 was independently isolated as an interacting partner of chicken ovalbumin upstream promoter transcription factor (COUP-TF) in neurons and as a tumor suppressor gene in mouse models of gamma ray-induced thymic lymphomas (1-3). Besides its expression in the central nervous system (CNS), BCL11B was shown to be widely expressed in all T-cell subsets, starting from the double-negative stage 2 (DN2 stage) and to be involved in various aspects of development, function, and survival of T cells (4). Indeed, BCL11B is a focal point essential for several checkpoints involved in T-cell commitment in early progenitors, selection at the DN2 stage, and differentiation of peripheral T cells (5-9). Furthermore, monoallelic BCL11B deletions or missense mutations have been identified in the major molecular subtypes of T-cell acute lymphoblastic leukemia (10). Therefore, these observations together with the occurrence of deletions and mutations in gamma ray-induced thymomas in mice identify BCL11B as a haploinsufficient tumor suppressor gene (11).BCL11B is essential for T-cell development and is considered a "guardian of T cell fate" (12). Its closely related paralog BCL11A is essential for normal lymphopoiesis and hemoglobin switching during erythroid differentiation (13-15). Thus, these two transcription factors appear to be key regulators of fundamental differentiation programs during normal hematopoiesis.BCL11B represses transcription of its target genes through interaction with several chromatin remodelling complexes and notably recruits NuRD complexes (nuclear remodeling and deacetylation complexes) via interaction with MTA1 and MTA2 (4,11,[16][17][18]. Although originally characterized as a sequence-specific transcriptional repressor, BCL11B also behaves as a context-dependent transcriptional activator of the IL-2 and Cot kinase genes in CD4 ϩ T-cell activation (19, 20). This dual behavior of BCL11B as a transcriptional repressor and activator is not fully understood but clearly relies on a dynamic cross talk between BCL11B PTMs. Indeed, mass spectrometry analyses of thymocytes isolated from 4-to 8-week-old mice and stimulated with a mixture of phorbol ester and calcium ionophore used as an in vitro model mimicking T-cell receptor (TCR) activation identified several mitogen-activated protein kinase (MAPK) phosphorylation sites of BCL11B and confirmed its

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“…Thus, Bcl11b regulates some common themes in some immune populations, such as ILCs and iNKT cells, however, it acts also in a context-dependent manner in other populations (reviewed in ref. 42). It remains to be established whether Bcl11b plays other roles in iNKT17 cells except restricting expression of its signature genes.…”

Section: Discussionmentioning

confidence: 99%

“…42). Both Nkp46 and Gzmb were very modestly expressed in the wild-type thymic and splenic iNKT cells at steady state (Fig.…”

Section: Bcl11b Restricts Expression Of Inkt17 Program In Inkt1 and Imentioning

confidence: 99%

Transcription factor Bcl11b sustains iNKT1 and iNKT2 cell programs, restricts iNKT17 cell program, and governs iNKT cell survival

Uddin

Sultana

Lorentsen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Invariant natural killer T (iNKT) cells are innate-like T cells that recognize glycolipid antigens and play critical roles in regulation of immune responses. Based on expression of the transcription factors (TFs) Tbet, Plzf, and Rorγt, iNKT cells have been classified in effector subsets that emerge in the thymus, namely, iNKT1, iNKT2, and iNKT17. Deficiency in the TF Bcl11b in double-positive (DP) thymocytes has been shown to cause absence of iNKT cells in the thymus and periphery due to defective self glycolipid processing and presentation by DP thymocytes and undefined intrinsic alterations in iNKT precursors. We used a model of cre-mediated postselection deletion of Bcl11b in iNKT cells to determine its intrinsic role in these cells. We found that Bcl11b is expressed equivalently in all three effector iNKT subsets, and its removal caused a reduction in the numbers of iNKT1 and iNKT2 cells, but not in the numbers of iNKT17 cells. Additionally, we show that Bcl11b sustains subset-specific cytokine production by iNKT1 and iNKT2 cells and restricts expression of iNKT17 genes in iNKT1 and iNKT2 subsets, overall restraining the iNKT17 program in iNKT cells. The total numbers of iNKT cells were reduced in the absence of Bcl11b both in the thymus and periphery, associated with the decrease in iNKT1 and iNKT2 cell numbers and decrease in survival, related to changes in survival/apoptosis genes. Thus, these results extend our understanding of the role of Bcl11b in iNKT cells beyond their selection and demonstrate that Bcl11b is a key regulator of iNKT effector subsets, their function, identity, and survival.iNKT cell program | transcription factor Bcl11b | iNKT1 effector cells | iNKT2 effector cells | iNKT17 effector cells

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The Multifaceted Roles of Bcl11b in Thymic and Peripheral T Cells: Impact on Immune Diseases

Cited by 88 publications

References 62 publications

Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

Protein Kinase C-Mediated Phosphorylation of BCL11B at Serine 2 Negatively Regulates Its Interaction with NuRD Complexes during CD4⁺ T-Cell Activation

Transcription factor Bcl11b sustains iNKT1 and iNKT2 cell programs, restricts iNKT17 cell program, and governs iNKT cell survival

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The Multifaceted Roles of Bcl11b in Thymic and Peripheral T Cells: Impact on Immune Diseases

Cited by 88 publications

References 62 publications

Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

Protein Kinase C-Mediated Phosphorylation of BCL11B at Serine 2 Negatively Regulates Its Interaction with NuRD Complexes during CD4+ T-Cell Activation

Transcription factor Bcl11b sustains iNKT1 and iNKT2 cell programs, restricts iNKT17 cell program, and governs iNKT cell survival

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Protein Kinase C-Mediated Phosphorylation of BCL11B at Serine 2 Negatively Regulates Its Interaction with NuRD Complexes during CD4⁺ T-Cell Activation