Transcription Factor Bcl11b Controls Identity and Function of Mature Type 2 Innate Lymphoid Cells

Califano, Danielle; Cho, Jonathan; Uddin, M. Rakib; Lorentsen, Kyle J.; Yang, Qi; Bhandoola, Avinash; Li, Hongmin; Avram, Dorina

doi:10.1016/j.immuni.2015.07.005

Cited by 145 publications

(164 citation statements)

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“…Also, Id2 is very easily up-regulated with any reduction of Bcl11b level, suggesting that Bcl11b may only weakly repress this gene. Recently, too, the type 2 ILC lineage has been shown to depend on Bcl11b as well as on Id2 (11,32,33), proving that the two can be coexpressed. Most genes de-repressed in Bcl11b KOs (Datasets S1 and S2) are more typical of NK, ILC1, and ILC3 cells than of ILC2 cells (54,56), suggesting that low levels of Bcl11b may block these alternatives while still allowing Id2 expression in ILC2 cells.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

“…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: 98%

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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“…Therefore, consistently with their expression patterns, Runx1 and Runx3 appear to cooperate in regulating T-cell development at multiple stages; Runx1 is more important during early development of thymic precursors (DN and DP) while Runx3 becomes a CD8-lineage commitment factor (CD8 SP) [44]. Bcl11b is expressed mainly in T cells in mice, but recent studies showed that Bcl11b is also expressed in innate lymphoid cells [45]. During thymocyte differentiation, expression of Bcl11b is rapidly induced from DN2a stage, and it plays an important role in T-cell specification by driving DN2a cells into DN2b stage partly by upregulating some essential components of pre-TCR such as Zap70 and Ptcr-α but not .…”

mentioning

confidence: 85%

“…Bcl11b is expressed mainly in T cells in mice, but recent studies showed that Bcl11b is also expressed in innate lymphoid cells [45]. During thymocyte differentiation, expression of Bcl11b is rapidly induced from DN2a stage, and it plays an important role in T-cell specification by driving DN2a cells into DN2b stage partly by upregulating some essential components of pre-TCR such as Zap70 and Ptcr-α but not CD3 and RAG-1 [46].…”

Section: Role Of Transcription Factors In Early T-cell Developmentmentioning

confidence: 99%

Transcriptional regulation of early T‐cell development in the thymus

Seo

Taniuchi

2016

Eur J Immunol

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T-cell development occurs in multipotent progenitors arriving in the thymus, which provides a highly specialized microenvironment. Specification and sequential commitment processes to T cells begin in early thymic progenitors upon receiving thymus-specific environmental cues, resulting in the activation of the genetically programmed transcriptional cascade that includes turning on and off numerous transcription factors in a precise manner. Thus, early thymocyte differentiation has been an excellent model system to study cell differentiation processes. This review summarizes recent advances in our knowledge on thymic T-cell development from newly arrived multipotent T-cell progenitors to fully committed T-cell precursors, from the transcriptional regulation perspective. Keywords: T-cell development r Thymus r Transcription factors r Transcriptional regulation r Transcriptional network r T-cell progenitors IntroductionDevelopment requires a complex but precise control of regulatory genes and the regulation of individual gene expression can be achieved by numerous mechanisms such as transcriptional regulation, post-transcriptional modifications, and translational regulation. However, regulation at the transcriptional level is not only the most fundamental since transcription is the first step during gene expression but also the most energy-efficient method since mRNAs are not synthesized at all until required [1]. At the most basic level, transcriptional regulation is achieved at the transcription initiation stage by the interaction of two entities, cis-acting elements of regulatory DNA sequences, such as promoters, enhancers, and silencers, and trans-acting factors of proteins such as transcription factors. A specific interaction between cognate cis-and trans-factors is followed by the recruitment of more general machineries such as transcriptional activators and repressors [2]. Although the basic mechanism of transcriptional regulation by cis-elements and transcription factors is similar, the genomic structure of eukaryotes is far more complex than that of Correspondence: Dr. Wooseok Seo e-mail: wooseok.seo@riken.jp prokaryotes. For example, eukaryotic cis-regulatory DNA elements are not only found in the vicinity of the target gene but can also be present far away from the transcriptional start site, an example is a cluster of cis-elements for Shh (The sonic hedgehog) pathway, which is located 1000 kb away [3]. Therefore, in some cases, regulation of gene expression in eukaryotes inevitably requires long-range interactions between specific DNA sequences, which allow them to be positioned in close proximity to each other. Even though such tertiary structures can be achieved by a variety of mechanisms, including self-association of CCCTC-binding factor (CTCF) proteins bound on insulator sequences or interaction between mediator complexes bound on cis-elements [4], the underlying common scheme is the establishment of chromatin looping.Interactions between transcription factors and cis-elements, as well as chromatin...

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“…Additionally, Bcl11b restricts expression of Th2 lineage genes in Th17 cells in experimental autoimmune encephalomyelitis (EAE) (33). Bcl11b was recently found to sustain innate lymphoid type 2 cell (ILC2) program (34,35,36) and to suppress ILC3 program in ILC2s…”

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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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Transcription Factor Bcl11b Controls Identity and Function of Mature Type 2 Innate Lymphoid Cells

Cited by 145 publications

References 50 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

Transcriptional regulation of early T‐cell development in the thymus

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

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