Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation

Lin, Chih‐Chung; Bradstreet, Tara R.; Schwarzkopf, Elizabeth A.; Sim, Julia; Carrero, Javier A.; Chou, Chun; Cook, Lindsey E.; Egawa, Takeshi; Taneja, Reshma; Murphy, Theresa L.; Russell, John H.; Edelson, Brian T.

doi:10.1038/ncomms4551

Cited by 148 publications

(191 citation statements)

References 70 publications

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“…However, no significant changes in Bhlhe40 mRNA expression were observed in iNKT cells of mice subjected to dark/light cycles, suggesting that the functions of Bhlhe40 in iNKT cells are independent of the circadian rhythm. Bhlhe40 was shown to control various functions of T cells, such as turning of naïve CD8 + T cells into memory ones, cytokine productions, or tumor infiltration, in a circadian rhythm-independent manner (43)(44)(45). Similarly, in this study, we report a previously unidentified function for Bhlhe40 as an enhancer of IFN-γ production in iNKT cells that is also independent of the circadian rhythm.…”

Section: Bhlhe40 -/-Inktsupporting

confidence: 73%

“…As suggested by other reports, the deficiency of Bhlhe40 results in decreased IFN-γ production from Th1 cells (43). Bhlhe40 −/− mice showed a resistance to the induction of experimental autoimmune encephalomyelitis, which is mediated by Th1 and Th17 cells (43).…”

Section: Bhlhe40 -/-Inktmentioning

confidence: 59%

“…Bhlhe40 −/− mice showed a resistance to the induction of experimental autoimmune encephalomyelitis, which is mediated by Th1 and Th17 cells (43). On the other hand, T-bet-expressing natural killer cells and γδ-T cells are also known to rapidly produce large amounts of IFN-γ following stimulation.…”

Section: Bhlhe40 -/-Inktmentioning

confidence: 99%

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Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production iniNKT cells

Kanda

Yamanaka

Kojo

et al. 2016

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

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Invariant natural killer T (iNKT) cells are a subset of innate-like T cells that act as important mediators of immune responses. In particular, iNKT cells have the ability to immediately produce large amounts of IFN-γ upon activation and thus initiate immune responses in various pathological conditions. However, molecular mechanisms that control IFN-γ production in iNKT cells are not fully understood. Here, we report that basic helix-loop-helix transcription factor family, member e40 (Bhlhe40), is an important regulator for IFN-γ production in iNKT cells. Bhlhe40 is highly expressed in stage 3 thymic iNKT cells and iNKT1 subsets, and the level of Bhlhe40 mRNA expression is correlated with Ifng mRNA expression in the resting state. Although Bhlhe40-deficient mice show normal iNKT cell development, Bhlhe40-deficient iNKT cells show significant impairment of IFN-γ production and antitumor effects. Bhlhe40 alone shows no significant effects on Ifng promoter activities but contributes to enhance T-box transcription factor Tbx21 (T-bet)-mediated Ifng promoter activation. Chromatin immunoprecipitation analysis revealed that Bhlhe40 accumulates in the T-box region of the Ifng locus and contributes to histone H3-lysine 9 acetylation of the Ifng locus, which is impaired without T-bet conditions. These results indicate that Bhlhe40 works as a cofactor of T-bet for enhancing IFN-γ production in iNKT cells.

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Section: Bhlhe40 -/-Inktsupporting

confidence: 73%

Section: Bhlhe40 -/-Inktmentioning

confidence: 59%

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Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production iniNKT cells

Kanda

Yamanaka

Kojo

et al. 2016

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

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“…Several individual transcripts overabundant in Klrc1 −/− cells were indicative of CD8 + T cell activation, including Ifng, Prf1, Rel, Batf3 , and Bhlhe40 (Figure 4F). Upregulation of Bhlhe40 most likely explains the augmented production of GM-CSF by virus-specific Klrc1 −/− CD8 + T cells, as Bhlhe40 positively regulates the production of GM-CSF (Lin et al, 2014). Importantly, Klrc1 −/− cells also overexpressed Bcl2l11 , which encodes Bim, a key pro-apoptotic mediator.…”

Section: Resultsmentioning

confidence: 99%

The Inhibitory Receptor NKG2A Sustains Virus-Specific CD8+ T Cells in Response to a Lethal Poxvirus Infection

et al. 2015

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Summary CD8+ T cells and NK cells protect from viral infections by killing virally-infected cells and secreting interferon-γ. Several inhibitory receptors limit the magnitude and duration of these anti-viral responses. NKG2A, which is encoded by Klrc1, is a lectin-like inhibitory receptor that is expressed as a heterodimer with CD94 on NK cells and activated CD8+ T cells. Previous studies on the impact of CD94/NKG2A heterodimers on anti-viral responses have yielded contrasting results and the in vivo function of NKG2A remains unclear. Here, we generated Klrc1−/− mice and found that NKG2A is selectively required for resistance to ectromelia virus (ECTV). NKG2A functions intrinsically within ECTV-specific CD8+ T cells to limit excessive activation, prevent apoptosis, and preserve the specific CD8+ T cell response. Thus, while inhibitory receptors often cause T cell exhaustion and viral spreading during chronic viral infections, NKG2A optimizes CD8+ T cell responses during an acute poxvirus infection.

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“…In addition, disruption of NF-κB2, a component of the noncanonical NF-κB pathway, resulted in impaired GM-CSF expression by inflammatory T cells and protected mice from EAE [21]. Deficiency of Bhlhe40, a helix-loop-helix transcription factor that is required for GM-CSF expression in effector T cells, also resulted in resistance to MOGinduced EAE [22,23]. In addition, deletion of either STAT5 or STAT4 leads to impaired GM-CSF production by CD4 + T cells and caused resistance to EAE [24,25].…”

Section: Th Cell-derived Gm-csf In Autoimmune Neuronal Diseasementioning

confidence: 99%

T Cell-Derived GM-CSF, Regulation of Expression and Function

Sheng¹,

Png²,

Reynolds³

et al. 2015

Immunome Res

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is produced by a variety of cells and plays an important role in the inflammatory response in infection as well as in autoimmunity. Recent progress has indicated that CD4 + T cell-derived GM-CSF has a prominent and non-redundant function in mediating autoimmune neuroinflammation. Thus, there is increased interest in the regulation of GM-CSF production by T helper cells, which could translate to the development of novel therapeutics for autoimmune diseases such as multiple sclerosis. This review focuses on our current understanding of the regulation and function of T cell-derived GM-CSF.

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Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation

Cited by 148 publications

References 70 publications

Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production iniNKT cells

Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production iniNKT cells

The Inhibitory Receptor NKG2A Sustains Virus-Specific CD8+ T Cells in Response to a Lethal Poxvirus Infection

T Cell-Derived GM-CSF, Regulation of Expression and Function

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