Follicular regulatory T cells inhibit the development of granzyme B–expressing follicular helper T cells

Xie, Markus M.; Fang, Shuyi; Chen, Qiang; Liu, Hong; Wan, Jun; Dent, Alexander L.

doi:10.1172/jci.insight.128076

Cited by 55 publications

(60 citation statements)

References 32 publications

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“…RNA sequencing has demonstrated that Tfr cells inhibit the development of a cytotoxic‐like Tfh‐cell subset that highly expresses Eomes proteins and granzyme B in Tfr cell–deficient ( Bcl6‐flox/Foxp3‐cre ) and Tfr cell–amplified ( Blimp1‐flox/Foxp3‐cre ) mouse strains . Since abnormal cytotoxic Tfh cells are associated with an attenuated GC and antibody responses, Tfr cells are expected to have the potential to help the GC responses.…”

Section: Mechanisms Of Tfr‐cell Effector Functionmentioning

confidence: 99%

“…Once patients get relief after allergen immunotherapy, the frequency and function of cTfr cells are recovered . Tfr cells have also been investigated in a food allergy mouse model to measure peanut‐specific antibody responses …”

Section: Tfr Cells In Human Diseases and Animal Modelsmentioning

confidence: 99%

“…Furthermore, Tfr cells help maintain high levels of high‐affinity antigen‐specific antibodies and regulate the isotype switch of antibodies . They also promote the GC response through the secretion of IL‐10 and the suppression of cytotoxic Tfh cells . Thus, Tfr cells might play a complicated role in the fine‐tuning of GC response and act as ‘helper cells’ in certain scenarios.…”

Section: Challenges and Unsolved Questions Of Tfr Cellsmentioning

confidence: 99%

“…92 Tfr cells have also been investigated in a food allergy mouse model to measure peanut-specific antibody responses. 53…”

Section: Tfr Cells In Allergiesmentioning

confidence: 99%

“…45 They also promote the GC response through the secretion of IL-10 and the suppression of cytotoxic Tfh cells. 53,57 Thus, Tfr cells might play a complicated role in the fine-tuning of GC response and act as 'helper cells' in certain scenarios.…”

Section: Challenges and Unsolved Questions Of Tfr Cellsmentioning

confidence: 99%

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Follicular regulatory T cells: a novel target for immunotherapy?

et al. 2020

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High‐affinity antibodies are produced during multiple processes in germinal centres (GCs), where follicular helper T (Tfh) cells interact closely with B cells to support B‐cell survival, differentiation and proliferation. Recent studies have revealed that a specialised subset of regulatory T cells, follicular regulatory T (Tfr) cells, especially fine‐tune Tfh cells and GC B cells, ultimately regulating GC reactions. Alterations in frequencies or function of Tfr cells may result in multiple autoantibody‐mediated or autoantibody‐associated diseases. This review discusses recent insights into the physiology and pathology of Tfr cells, with a special emphasis on their potential roles in human diseases. Discrepancies are common among studies, reflecting the limited understanding of Tfr cells. Further exploration of the mechanisms of Tfr cells in these diseases and thus targeting Tfr cells may help reinstate immune homeostasis and provide novel immunotherapy.

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Section: Mechanisms Of Tfr‐cell Effector Functionmentioning

confidence: 99%

Section: Tfr Cells In Human Diseases and Animal Modelsmentioning

confidence: 99%

Section: Challenges and Unsolved Questions Of Tfr Cellsmentioning

confidence: 99%

“…92 Tfr cells have also been investigated in a food allergy mouse model to measure peanut-specific antibody responses. 53…”

Section: Tfr Cells In Allergiesmentioning

confidence: 99%

Section: Challenges and Unsolved Questions Of Tfr Cellsmentioning

confidence: 99%

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Follicular regulatory T cells: a novel target for immunotherapy?

et al. 2020

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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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New insights into follicular regulatory T cells in the intestinal and tumor microenvironments

Cao

Hou

Zhao

et al. 2023

Journal Cellular Physiology

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Follicular regulatory T (Tfr) cells are a novel and unique subset of effector regulatory T (Treg) cells that are located in germinal centers (GCs). Tfr cells express transcription profiles that are characteristic of both follicular helper T (Tfh) cells and Treg cells and negatively regulate GC reactions, including Tfh cell activation and cytokine production, class switch recombination and B cell activation. Evidence also shows that Tfr cells have specific characteristics in different local immune microenvironments. This review focuses on the regulation of Tfr cell differentiation and function in unique local immune microenvironments, including the intestine and tumor.

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Follicular regulatory T cells inhibit the development of granzyme B–expressing follicular helper T cells

Cited by 55 publications

References 32 publications

Follicular regulatory T cells: a novel target for immunotherapy?

Follicular regulatory T cells: a novel target for immunotherapy?

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

New insights into follicular regulatory T cells in the intestinal and tumor microenvironments

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