Stepwise Tfh cell differentiation revisited: new advances and long-standing questions

Schroeder, Andrew R.; Zhu, Fangming; Hu, Hui

doi:10.12703/r/10-3

Cited by 7 publications

(5 citation statements)

References 172 publications

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“…Studies have shown that dendritic cells are sufficient to prime naïve CD4 + T cells to generate PD-1 + CXCR5 + Bcl6 + cells 9 , which then require interactions with B cells to become PD-1 hi CXCR5 hi Bcl6 hi GC-Tfh cells 4,[9][10][11] . Although it has been suggested that not all the activated PD-1 + CXCR5 + CD4 + T cells will enter B cell follicles and become GC-Tfh cells, and there are follicular helper-like central memory CD4 + T cells expressing CXCR5 and CCR7 12,13 , it is not known how to distinguish which PD-1 + CXCR5 + CD4 + T cells will enter B cell follicles and become GC-Tfh cells while others have a different fate 14 .…”

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confidence: 99%

Spatiotemporal resolution of germinal center Tfh cell differentiation and divergence from central memory CD4+ T cell fate

Zhu,

McMonigle,

Schroeder

et al. 2023

Nat Commun

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Follicular helper T (Tfh) cells are essential for germinal center (GC) B cell responses. However, it is not clear which PD-1+CXCR5+Bcl6+CD4+ T cells will differentiate into PD-1hiCXCR5hiBcl6hi GC-Tfh cells and how GC-Tfh cell differentiation is regulated. Here, we report that the sustained Tigit expression in PD-1+CXCR5+CD4+ T cells marks the precursor Tfh (pre-Tfh) to GC-Tfh transition, whereas Tigit–PD-1+CXCR5+CD4+ T cells upregulate IL-7Rα to become CXCR5+CD4+ T memory cells with or without CCR7. We demonstrate that pre-Tfh cells undergo substantial further differentiation at the transcriptome and chromatin accessibility levels to become GC-Tfh cells. The transcription factor c-Maf appears critical in governing the pre-Tfh to GC-Tfh transition, and we identify Plekho1 as a stage-specific downstream factor regulating the GC-Tfh competitive fitness. In summary, our work identifies an important marker and regulatory mechanism of PD-1+CXCR5+CD4+ T cells during their developmental choice between memory T cell fate and GC-Tfh cell differentiation.

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confidence: 99%

Spatiotemporal resolution of germinal center Tfh cell differentiation and divergence from central memory CD4+ T cell fate

Zhu,

McMonigle,

Schroeder

et al. 2023

Nat Commun

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“…In these as well as in TFHL-AI-2 cases with predominantly extrafollicular involvement, a functionally defective CXCR5 molecule or dysregulated migratory machinery may be the explanation. Circulating CXCR5+ T helper cells in the blood, representing memory TFH cells and mature TFH cells located in the B-cell follicles of secondary lymphoid follicles, have been characterized [ 10 , 19 , 28 , 29 ], but the spatiotemporal determinants of migration in lymph nodes and other secondary lymphoid organs, from the HEV passage to the follicular entry, have not been fully elucidated [ 11 , 29 , 30 , 31 ]. CXCR5 is necessary but not sufficient for the follicular homing of TFH cells.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Follicular Helper T-Cell Markers with the Expression of the Follicular Homing Marker CXCR5 in Peripheral T-Cell Lymphomas—A Reappraisal of Follicular Helper T-Cell Lymphomas

Krenács,

Borbényi

et al. 2023

IJMS

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Peripheral T-cell lymphomas (PTCLs) expressing multiple follicular T helper (TFH) cell-related antigens are now classified as TFH lymphomas (TFHL), including angioimmunoblastic, follicular, and not otherwise specified (NOS) types. CXCR5 is the TFH cell-defining chemokine receptor that, together with its ligand CXCL13, plays a critical role in the development of follicles and the positioning of TFH and B cells within follicles. A comprehensive immunomorphologic study was performed to investigate the expression pattern of CXCR5 in a large cohort of nodal PTCLs, particularly those with a TFH cell phenotype, and to compare its expression with six other TFH cell-related antigens. We found that CXCR5 is widely expressed in neoplastic TFH cells, except in TFHL-NOS, and represents a specific marker of this lymphoma entity. Our results suggest that CXCR5 directs the distribution of neoplastic T cells in the affected lymph nodes and may influence the formation of the pathognomic pathological FDC network.

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“…Since BCL6 was identified to be the master transcription factor in T FH cell differentiation, plenty of transcription factors have been discovered to regulate T FH cell differentiation via directly or indirectly affecting BCL6 expression and function ( Vinuesa et al., 2016 ; Choi et al., 2020 ; Schroeder et al., 2021 ). TCF1 and LEF1 initiate and promote T FH cell differentiation by ensuring the early expression of BCL6 and the repression of Blimp-1 ( Choi et al., 2015 ; Wu et al., 2015 ; Xu et al., 2015 ).…”

Section: Virus-specific T Fh Cell Differentiationmentioning

confidence: 99%

The Differentiation and Maintenance of SARS-CoV-2-Specific Follicular Helper T Cells

Wang

Qin²,

Ye³

2022

Front. Cell. Infect. Microbiol.

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Upon acute viral infection, virus-specific CD4+ T cells differentiate into either TH1 cells or follicular helper T (TFH) cells. The molecular pathways governing such bimodal cell fate commitment remain elusive. Additionally, effector virus-specific TFH cells further differentiate into corresponding memory population, which confer long-term protection against re-infection of same viruses by providing immediate help to virus-specific memory B cells. Currently, the molecular mechanisms underlying the long-term maintenance of memory TFH cells are largely unknown. In this review, we discuss current understanding of early differentiation of virus-specific effector TFH cells and long-term maintenance of virus-specific memory TFH cells in mouse models of viral infection and patients of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

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Stepwise Tfh cell differentiation revisited: new advances and long-standing questions

Cited by 7 publications

References 172 publications

Spatiotemporal resolution of germinal center Tfh cell differentiation and divergence from central memory CD4+ T cell fate

Spatiotemporal resolution of germinal center Tfh cell differentiation and divergence from central memory CD4+ T cell fate

Comparison of Follicular Helper T-Cell Markers with the Expression of the Follicular Homing Marker CXCR5 in Peripheral T-Cell Lymphomas—A Reappraisal of Follicular Helper T-Cell Lymphomas

The Differentiation and Maintenance of SARS-CoV-2-Specific Follicular Helper T Cells

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