Bcl-6 is the nexus transcription factor of T follicular helper cells via repressor-of-repressor circuits

Choi, Jinyong; Diao, Huitian; Faliti, Caterina E.; Truong, Jacquelyn; Rossi, Meghan; Bélanger, Simon; Yu, Bingfei; Goldrath, Ananda W.; Pipkin, Matthew E.; Crotty, Shane

doi:10.1038/s41590-020-0706-5

Cited by 96 publications

(165 citation statements)

References 61 publications

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“…25 As discussed below, this study confirmed previous work highlighting that Bcl6 acts as a hub for the transcriptional repression of pathways that inhibit Tfh differentiation. 25 Importantly, this and other studies have recently demonstrated that Bcl6 repression of these transcriptional networks occurs independently of Blimp-1, further highlighting the indispensable role for Bcl6 in Tfh fate commitment. 25,26 Several unique structural features of the Bcl6 protein allow it to interact with diverse transcription factors and chromatin modifiers to form transcriptional complexes.…”

Section: Bcl6supporting

confidence: 89%

“…25 Importantly, this and other studies have recently demonstrated that Bcl6 repression of these transcriptional networks occurs independently of Blimp-1, further highlighting the indispensable role for Bcl6 in Tfh fate commitment. 25,26 Several unique structural features of the Bcl6 protein allow it to interact with diverse transcription factors and chromatin modifiers to form transcriptional complexes. These interactions permit Bcl6 to control gene expression in CD4 + T-cell precursors and in mature Tfh cells.…”

Section: Bcl6mentioning

confidence: 53%

“…11 The overexpression of Blimp-1 inhibits CD4 + T cells to acquire the Tfh phenotype by inhibiting the expression of canonical markers, including CXCR5, ICOS, and PD-1. 11,21,23,25 While it was previously proposed that Tfh cell formation was a default differentiation state for CD4 + T cells, this has recently been shown to not be the case, as cells deficient in both Bcl6 and Blimp-1 fail to form Tfh cells in vivo following both immunization and viral infection. 25 As discussed below, this study confirmed previous work highlighting that Bcl6 acts as a hub for the transcriptional repression of pathways that inhibit Tfh differentiation.…”

Section: Bcl6mentioning

confidence: 99%

“…11,21,23,25 While it was previously proposed that Tfh cell formation was a default differentiation state for CD4 + T cells, this has recently been shown to not be the case, as cells deficient in both Bcl6 and Blimp-1 fail to form Tfh cells in vivo following both immunization and viral infection. 25 As discussed below, this study confirmed previous work highlighting that Bcl6 acts as a hub for the transcriptional repression of pathways that inhibit Tfh differentiation. 25 Importantly, this and other studies have recently demonstrated that Bcl6 repression of these transcriptional networks occurs independently of Blimp-1, further highlighting the indispensable role for Bcl6 in Tfh fate commitment.…”

Section: Bcl6mentioning

confidence: 99%

“…While N-COR and SMRT are also expressed in CD4 + T cells, further research is needed to determine their role in Tfh differentiation; however, recently, N-COR was shown to be recruited to the Bcl6 promoter to negatively regulate Bcl6 expression. 25 Bcl6 utilizes its largest domain, the RDII domain, to associate with the corepressor MTA3. This interaction leads to the repression of Blimp-1.…”

Section: Bcl6mentioning

confidence: 99%

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Transcription tipping points for T follicular helper cell and T-helper 1 cell fate commitment

Sheikh

Groom

2020

Cell Mol Immunol

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During viral infection, immune cells coordinate the induction of inflammatory responses that clear infection and humoral responses that promote protection. CD4+ T-cell differentiation sits at the center of this axis. Differentiation toward T-helper 1 (Th1) cells mediates inflammation and pathogen clearance, while T follicular helper (Tfh) cells facilitate germinal center (GC) reactions for the generation of high-affinity antibodies and immune memory. While Th1 and Tfh differentiation occurs in parallel, these CD4+ T-cell identities are mutually exclusive, and progression toward these ends is determined via the upregulation of T-bet and Bcl6, respectively. These lineage-defining transcription factors act in concert with multiple networks of transcriptional regulators that tip the T-bet and Bcl6 axis in CD4+ T-cell progenitors to either a Th1 or Tfh fate. It is now clear that these transcriptional networks are guided by cytokine cues that are not only varied between distinct viral infections but also dynamically altered throughout the duration of infection. Thus, multiple intrinsic and extrinsic factors combine to specify the fate, plasticity, and function of Th1 and Tfh cells during infection. Here, we review the current information on the mode of action of the lineage-defining transcription factors Bcl6 and T-bet and how they act individually and in complex to govern CD4+ T-cell ontogeny. Furthermore, we outline the multifaceted transcriptional regulatory networks that act upstream and downstream of Bcl6 and T-bet to tip the differentiation equilibrium toward either a Tfh or Th1 fate and how these are impacted by dynamic inflammatory cues.

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Section: Bcl6supporting

confidence: 89%

Section: Bcl6mentioning

confidence: 53%

Section: Bcl6mentioning

confidence: 99%

Section: Bcl6mentioning

confidence: 99%

Section: Bcl6mentioning

confidence: 99%

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Transcription tipping points for T follicular helper cell and T-helper 1 cell fate commitment

Sheikh

Groom

2020

Cell Mol Immunol

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PIP2 Alteration Caused by Elastic Modulus and Tropism of Electrospun Scaffolds Facilitates Altered BMSCs Proliferation and Differentiation

et al. 2023

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engineering and stem cell therapy. [3][4][5] There is increasing evidence that biomaterial surface topography is an essential factor that selectively influences cell adhesion and, in some cases, promotes cell differentiation. [6] To date, various biomaterials with different topographies at both the micrometer and nanometer scales, such as columns, grooves, and submicron fibers, have been applied to study the influence of topography on cellular functions. [7] Electrospun submicron fibers have been extensively explored as scaffolds to manipulate cell migration owing to their unique characteristics in mimicking the hierarchical architecture of the extracellular matrix. [8] In particular, aligned electrospun submicron fibers arrays can guide and promote the directional migration of cells. [9][10][11] Therefore, submicron fibers are widely applied to influence cell behavior. [12] Studies have indicated that fibroblasts on aligned substrates align themselves parallel with their substrate and increase production of the actin and focal adhesion-related genes. [13] Studies have stained neuronal differentiation marker proteins and found that neural stem cells aligned on submicron fibers had a higher differentiation rate than cells on random submicron fibers. [14] Although traditional molecular biology approaches have clearly shown that aligned submicron fibers can promote stem cell proliferation and differentiation, the mechanistic reasons for the differences between aligned and random fibers still need to be clarified. Since compositionally, dimensionally, geometrically, and morphologically controllable nanofibrous materials can be synthesized, many nanofibrous materials have been applied in biomedicine. [15,16] However, the hierarchical architecture structure is not destined to be designed into an aligned structure, leading to incomplete cell growth, a slow differentiation rate, and excessive waste of random materials. Therefore, it is essential to clarify the difference between the aligned and random structures and to reduce this difference.Researchers have found that miRNAs are essential factors in substance cell interactions. [17] MiRNAs are a class of endogenous noncoding small RNAs that bind to the 3′ untranslated regions of their target mRNAs, [18] leading to degradation or translational repression of these mRNAs, thereby regulating various cellular functions. [19] Recent studies have shown that miRNAs play Aligned submicron fibers have played an essential role in inducing stem cell proliferation and differentiation. In this study, it is aimed to identify the differential causes of stem cell proliferation and differentiation between bone marrow mesenchymal stem cells (BMSCs) on aligned-random fibers with different elastic modulus, and to change the differential levels through a regulatory mechanism mediated by B-cell lymphoma 6 protein(BCL-6) and miRNA-126-5p(miR-126-5p). The results showed that phosphatidylinositol(4,5)bisphosphate alterations are found in the aligned fibers compared with the random fibers, which ...

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The direct and indirect regulation of follicular T helper cell differentiation in inflammation and cancer

Cao

Lin

et al. 2021

Journal Cellular Physiology

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Follicular T helper (Tfh) cells play important roles in facilitating B‐cell differentiation and inducing the antibody response in humoral immunity and immune‐associated inflammatory diseases, including infections, autoimmune diseases, and cancers. However, Tfh cell differentiation is mainly achieved through self‐directed differentiation regulation and the indirect regulation mechanism of antigen‐presenting cells (APCs). During the direct intrinsic differentiation of naïve CD4+ T cells into Tfh cells, Bcl‐6, as the characteristic transcription factor, plays the core role of transcriptional regulation. APCs indirectly drive Tfh cell differentiation mainly by changing cytokine secretion mechanisms. Altered metabolic signaling is also critically involved in Tfh cell differentiation. This review summarizes the recent progress in understanding the direct and indirect regulatory signals and metabolic mechanisms of Tfh cell differentiation and function in immune‐associated diseases.

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Bcl-6 is the nexus transcription factor of T follicular helper cells via repressor-of-repressor circuits

Cited by 96 publications

References 61 publications

Transcription tipping points for T follicular helper cell and T-helper 1 cell fate commitment

Transcription tipping points for T follicular helper cell and T-helper 1 cell fate commitment

PIP2 Alteration Caused by Elastic Modulus and Tropism of Electrospun Scaffolds Facilitates Altered BMSCs Proliferation and Differentiation

The direct and indirect regulation of follicular T helper cell differentiation in inflammation and cancer

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