The transcription factor lymphoid enhancer factor 1 controls invariant natural killer T cell expansion and Th2-type effector differentiation

Carr, T. D.; Krishnamoorthy, Veena; Yu, Shuyang; Xue, Hai-Hui; Kee, Barbara L.; Verykokakis, Mihalis

doi:10.1084/jem.20141849

Cited by 60 publications

(68 citation statements)

References 48 publications

(104 reference statements)

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“…6). As shown above, the mRNA encoding Lef1, recently found to be essential for iNKT2 cells (25), was reduced (Fig. 3).…”

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

confidence: 69%

“…Not only were the iNKT1 and iNKT2 subsets numerically reduced, but the percentages of IFNγ-and IL-4-producing iNKT cells were also reduced within the iNKT1 and iNKT2 subsets, respectively, suggesting that iNKT1 and iNKT2 cells have functional alterations in the absence of Bcl11b. The TF Lef1, recently demonstrated to control Gata3 and IL-4 expression in iNKT2 cells (25), was not reduced in Bcl11b −/− iNKT2 cells. There was no reduction in Gata3 expression, suggesting that Bcl11b might be involved in the control of IL-4, independent of these transcriptional regulators.…”

Section: Discussionmentioning

confidence: 69%

“…However, there was no change in the mRNAs for Gata3 and Zbtb7b (Thpok) (Fig. 3), known to be downstream of Lef1 (25). The mRNAs for the TFs Rorγt (Rorc) and Sox4, known to be important for the iNKT17 subset, were upregulated (Fig.…”

Section: Bcl11b's Removal Is Specific For Inkt Cells In Bcl11bmentioning

confidence: 98%

“…3). The mRNAs for the TFs Zbtb16 (PLZF) and Lef1, important for iNKT2 subset (15,25), were also diminished, together with the mRNAs for the iNKT2 subset cytokines IL-4 and IL-13, and the receptor IL-4Rα. However, there was no change in the mRNAs for Gata3 and Zbtb7b (Thpok) (Fig.…”

Section: Bcl11b's Removal Is Specific For Inkt Cells In Bcl11bmentioning

confidence: 99%

“…Hobit controls maintenance of mature iNKT cells and their effector functions (24). Recently Lef1 was found to be essential for iNKT2 subset formation and function, and to regulate Gata3 and Thpok (25), both known to control CD4 + iNKT cells (26). TF Bcl11b plays a crucial role in T-cell lineage commitment (27,28), selection, differentiation, and survival of thymocytes (29,30), clonal expansion and effector function of CD8 + T cells (31), as well as suppression function of Treg cells (32).…”

mentioning

confidence: 99%

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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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“…6). As shown above, the mRNA encoding Lef1, recently found to be essential for iNKT2 cells (25), was reduced (Fig. 3).…”

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

confidence: 69%

Section: Discussionmentioning

confidence: 69%

Section: Bcl11b's Removal Is Specific For Inkt Cells In Bcl11bmentioning

confidence: 98%

Section: Bcl11b's Removal Is Specific For Inkt Cells In Bcl11bmentioning

confidence: 99%

mentioning

confidence: 99%

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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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RhoA/Rho‐kinases in asthma: from pathogenesis to therapeutic targets

et al. 2020

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Asthma is a chronic and heterogeneous disease characterised by airway inflammation and intermittent airway narrowing. The key obstacle in the prevention and treatment of asthma has been our incomplete understanding of its aetiology and biological mechanisms. The ras homolog family member A (RhoA) of the Rho family GTPases has been considered to be one of the most promising and novel therapeutic targets for asthma. It is well known that RhoA/Rho-kinases play an important role in the pathophysiology of asthma, including airway smooth muscle contraction, airway hyper-responsiveness, b-adrenergic desensitisation and airway remodelling. However, recent advances have suggested novel roles for RhoA in regulating allergic airway inflammation. Specifically, RhoA has been shown to regulate allergic airway inflammation through controlling Th2 or Th17 cell differentiation and to regulate airway remodelling through regulating mesenchymal stem cell (MSC) differentiation. In this review, we evaluate the literature regarding the recent advances in the activation of RhoA/Rho-kinase, cytokine and epigenetic regulation of RhoA/Rho-kinase, and the role of RhoA/Rho-kinase in regulating major features of asthma, such as airway hyperresponsiveness, remodelling and inflammation. We also discuss the importance of the newly identified role of RhoA/Rho-kinase signalling in MSC differentiation and bronchial epithelial barrier dysfunction. These findings indicate the functional significance of the RhoA/Rho-kinase pathway in the pathophysiology of asthma and suggest that RhoA/Rho-kinase signalling may be a promising therapeutic target for the treatment of asthma.

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Applying the TOR(C)QUE in iNKT cells: A new twist in an old tale

Verykokakis

Kee

2017

Eur J Immunol

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The mammalian Target of Rapamycin (mTOR) protein controls the machinery necessary for T-cell activation, differentiation, and memory formation, as a component of mTOR complex 1 (mTORC1) and mTORC2, which function both downstream and upstream of AKT. Invariant natural killer T (iNKT) cells are a unique T-cell subset that exists in a primed state, capable of rapid activation, and produces large quantities of cytokines. iNKT-cell effector differentiation is dependent on the mTORC1 complex; however, the requirements for mTORC2 in iNKT cells have been controversial. In this issue, Sklarz et al. [Eur. J. Immunol. 2017. 47: XXX-XXX] provide a careful analysis of the requirements for the mTORC2 component Rictor in iNKT cells, providing a new twist in this unfolding tale. The authors demonstrate that Rictor is required for iNKT-cell proliferation and survival during the key stage of intrathymic expansion and that Rictor supports the development of NKT17 cells, an effector subset which depends on the transcription factor RORγt and produces interleukin (IL)-17, in both the thymus and the lung. IL-4-producing NKT2 cells develop in the absence of Rictor but the cytotoxic potential of iNKT cells is Rictor-dependent.

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The transcription factor lymphoid enhancer factor 1 controls invariant natural killer T cell expansion and Th2-type effector differentiation

Abstract: The transcription factor LEF1 promotes the expansion and Th2-type polarization of invariant NKT cells in part by directly inducing the expression of the IL-7 receptor component CD127 and the transcription factors c-myc and Gata3.

Cited by 60 publications

References 48 publications

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

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

RhoA/Rho‐kinases in asthma: from pathogenesis to therapeutic targets

Applying the TOR(C)QUE in iNKT cells: A new twist in an old tale

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