Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 Transcription Factor

Shen, Erxia; Rabe, Hardis; Luo, Lin; Wang, Lei; Wang, Qin; Yin, Jie; Yang, Xueying; Liu, Wenquan; Sido, Jessica M.; Nakagawa, Hidetoshi; Ao, Lin; Kim, Hye-Jung; Cantor, Harvey; Leavenworth, Jianmei W.

doi:10.1016/j.celrep.2019.10.012

Cited by 40 publications

(63 citation statements)

References 35 publications

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“…These data support the third explanation that Tfr cells have additional GCB cell helper activity besides that from IL-10. We should also note that, recently, Wang et al published a study indicating that Blimp1-deficient Tfr cells are unstable and can differentiate into IL-17-producing cells that can produce IL-4 and IL-21 and promote larger GCs (56). Although this model could explain the discrepancy of larger GCs despite depleted IL-10 production from the Tfr cells, we found no evidence in our RNA-Seq data of higher Il17 in Blimp1-deficient Tfr cells (Supplemental Figure 12).…”

Section: Methodsmentioning

confidence: 87%

T follicular regulatory cells and IL-10 promote food antigen–specific IgE

Xie¹,

Chen²,

Liu³

et al. 2020

Journal of Clinical Investigation

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Section: Methodsmentioning

confidence: 87%

T follicular regulatory cells and IL-10 promote food antigen–specific IgE

Xie¹,

Chen²,

Liu³

et al. 2020

Journal of Clinical Investigation

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“…The expression of pro-inflammatory cytokines by dysregulated Blimp1-deficient Tregs and T FR cells [ 11 ] led us to ask if Blimp1 expression in these cells may potentially regulate neuroinflammation. We then adopted the MOG 35-55 -induced EAE model [ 20 ] and mice harboring a deletion of Prdm1 in FoxP3 + T cells ( Prdm1 fl/fl FoxP3 Cre mice) [ 11 ] compared to FoxP3 YFP-Cre (WT) mice at 5–6 weeks old. Although there were insignificant differences of disease activity at the onset of EAE for both groups of mice, there were increased peak and overall disease severity for Prdm1 fl/fl FoxP3 YFP-Cre mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies have emphasized this critical aspect of T FR cells, as selective deletion of T FR cells has a profound impact on immune responses, leading to the aberrant expansion of T FH cells and excessive Ab production [ 10 ]. Like other Treg subsets, T FR cells must maintain their suppressive anergic phenotype during ongoing inflammatory responses and destabilized T FR cells become ex-T FR cells that acquire effector cell activity [ 11 – 13 ]. We have recently shown that Blimp1, a transcription factor (TF) marking effector Tregs, is essential to maintain T FR lineage stability, appropriate positioning in the GC, and effective regulatory activity [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…Like other Treg subsets, T FR cells must maintain their suppressive anergic phenotype during ongoing inflammatory responses and destabilized T FR cells become ex-T FR cells that acquire effector cell activity [ 11 – 13 ]. We have recently shown that Blimp1, a transcription factor (TF) marking effector Tregs, is essential to maintain T FR lineage stability, appropriate positioning in the GC, and effective regulatory activity [ 11 ]. Blimp1-deficient T FR cells, but not non-T FR Tregs, induce abnormal T FH -GC B expansion and autoantibody production by converting into effector T cells (Teff) that produce pro-inflammatory cytokines IL-17A and IFNγ [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…We have recently shown that Blimp1, a transcription factor (TF) marking effector Tregs, is essential to maintain T FR lineage stability, appropriate positioning in the GC, and effective regulatory activity [ 11 ]. Blimp1-deficient T FR cells, but not non-T FR Tregs, induce abnormal T FH -GC B expansion and autoantibody production by converting into effector T cells (Teff) that produce pro-inflammatory cytokines IL-17A and IFNγ [ 11 ]. However, we do not know how these Blimp1-deficient T FR cells, particularly those in the specific tissue lesions, respond to the pathological conditions, like neuroinflammation in the context of EAE.…”

Section: Introductionmentioning

confidence: 99%

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Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis

Luo

Dixon

et al. 2021

J Neuroinflammation

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Background Follicular regulatory T (TFR) cells are essential for the regulation of germinal center (GC) response and humoral self-tolerance. Dysregulated follicular helper T (TFH) cell-GC-antibody (Ab) response secondary to dysfunctional TFR cells is the root of an array of autoimmune disorders. The contribution of TFR cells to the pathogenesis of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis (EAE) remains largely unclear. Methods To determine the impact of dysregulated regulatory T cells (Tregs), TFR cells, and Ab responses on EAE, we compared the MOG-induced EAE in mice with a FoxP3-specific ablation of the transcription factor Blimp1 to control mice. In vitro co-culture assays were used to understand how Tregs and Ab regulate the activity of microglia and central nervous system (CNS)-infiltrating myeloid cells. Results Mice with a FoxP3-specific deletion of Blimp1 developed severe EAE and failed to recover compared to control mice, reflecting conversion of Tregs into interleukin (IL)-17A/granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing effector T cells associated with increased TFH-Ab responses, more IgE deposition in the CNS, and inability to regulate CNS CD11b+ myeloid cells. Notably, serum IgE titers were positively correlated with EAE scores, and culture of CNS CD11b+ cells with sera from these EAE mice enhanced their activation, while transfer of Blimp1-deficient TFR cells promoted Ab production, activation of CNS CD11b+ cells, and EAE. Conclusions Blimp1 is essential for the maintenance of TFR cells and Ab responses in EAE. Dysregulated TFR cells and Ab responses promote CNS autoimmunity.

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Conversion of T Follicular Helper Cells to T Follicular Regulatory Cells by Interleukin‐2 Through Transcriptional Regulation in Systemic Lupus Erythematosus

Nakayamada

Yamagata

et al. 2020

Arthritis & Rheumatology

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Objective. This study was undertaken to identify characteristics of follicular regulatory T (Tfr) cells and elucidate the mechanisms by which follicular helper T (Tfh) cells convert to Tfr cells. We probed the phenotype of T helper cells in patients with systemic lupus erythematosus (SLE) and underlying transcriptional regulation using cytokine-induced STAT family factors. Methods. Peripheral blood mononuclear cells from 41 patients with SLE and 26 healthy donors were used to sort out the memory Tfh cell subset, and Tfh cells were cultured under various conditions. The phenotype of T helper cells and underlying mechanisms of transcriptional regulation were probed using flow cytometry and quantitative polymerase chain reaction analyses. These analyses evaluated the expression of characteristic markers and phosphorylation of STATs. Chromatin immunoprecipitation was used to evaluate histone modifications. Results. In patients with SLE, the proportion of CD4+CXCR5+FoxP3-PD-1 high Tfh cells was increased (P < 0.01), whereas the proportion of CD4+CXCR5+CD45RA-FoxP3 high activated Tfr cells was decreased (P < 0.05). Serum interleukin-2 (IL-2) levels were also reduced in patients with SLE. IL-2 induced conversion of memory Tfh cells to functional Tfr cells, which was characterized by CXCR5+Bcl-6+FoxP3 high pSTAT3+pSTAT5+ cells. The loci of FOXP3 and BCL6 at STAT binding sites were marked by bivalent histone modifications. Following IL-2 stimulation, STAT3 and STAT5 selectively bound to FOXP3 and BCL6 gene loci accompanied by suppression of H3K27me3. Finally, IL-2 stimulation suppressed the generation of CD38+CD27 high plasmablasts in Tfh and B cell coculture assays ex vivo. Conclusion. Impaired function of Tfr cells might be attributed to defective IL-2 production. Exogenous IL-2 restores the function of Tfr cells through the conversion of Tfh cells to Tfr cells in patients with SLE. Thus, restoring balance between Tfh and Tfr cells may provide new therapeutic approaches in SLE.

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Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 Transcription Factor

Cited by 40 publications

References 35 publications

T follicular regulatory cells and IL-10 promote food antigen–specific IgE

T follicular regulatory cells and IL-10 promote food antigen–specific IgE

Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis

Conversion of T Follicular Helper Cells to T Follicular Regulatory Cells by Interleukin‐2 Through Transcriptional Regulation in Systemic Lupus Erythematosus

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