The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6

Stauss, Dennis; Brunner, Cornelia; Berberich‐Siebelt, Friederike; Höpken, Uta E.; Lipp, Martin; Müller, Gerd

doi:10.15252/embj.201591459

Cited by 42 publications

(66 citation statements)

References 77 publications

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“…Considering that Bcl-6 is the lineage-defining and functionally central transcription factor of Tfh cells, surprisingly little is known about its direct regulation. Although several transcription factors have been identified to promote early Tfh cell generation, only Tcf-1 and Bob1 have been shown to directly regulate Bcl-6 by binding to its promotor (42)(43)(44). In contrast, only STAT5 and Foxo1 were demonstrated to suppress Bcl-6 by direct binding to regulatory elements (45,46).…”

Section: Discussionmentioning

confidence: 99%

Bach2 Controls T Follicular Helper Cells by Direct Repression of Bcl-6

Lahmann

Kuhrau

Fuhrmann

et al. 2019

The Journal of Immunology

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T follicular helper (Tfh) cells are a specialized T cell subset that regulates the long-lived production of highly specific Abs by B cells during the germinal center (GC) reaction. However, the transcriptional network sustaining the Tfh cell phenotype and function is still incompletely understood. In this study, we identify the transcription factor Bach2 as a central negative regulator of Tfh cells. Ectopic overexpression of Bach2 in murine Tfh cells resulted in a rapid loss of their phenotype and subsequent breakdown of the GC response. Low Bach2 expression levels are required to maintain high expression of the signature cytokine IL-21, the coinhibitory receptor TIGIT and the transcriptional repressor Bcl-6. In stark contrast to the regulatory network in GC B cells, Bach2 in Tfh cells is not coexpressed with Bcl-6 at high levels to inhibit the antagonizing factor Blimp-1, but suppresses Bcl-6 by direct binding to the promoter. These data reveal that by replacing an activating complex of Batf and Irf-4 at the Bcl-6 promoter, Bach2 regulates the transcriptional network of Tfh cells in a different way, as in GC B cells.

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Section: Discussionmentioning

confidence: 99%

Bach2 Controls T Follicular Helper Cells by Direct Repression of Bcl-6

Lahmann

Kuhrau

Fuhrmann

et al. 2019

The Journal of Immunology

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“…2E). Interestingly, although POU2AF1 (encoding OCA-B), has been mainly characterised as a B-cell specific transcription factor in blood, where it plays a role in B-cell maturation (28), it has also been recently shown in mice to regulate the maintenance of memory phenotype and function in previously activated CD4 + T cells (29), and the differentiation of T follicular helper (Tfh) cells in the tissue (30). In agreement with this putative tissue-resident phenotype, pseudotime analysis demonstrated that these cells correspond to a highly differentiated cell state (Fig.…”

Section: Multi-omics Immunophenotyping Approach Identifies Rare Populmentioning

confidence: 99%

Discovery of CD80 and CD86 as recent activation markers on regulatory T cells by protein-RNA single-cell analysis

Trzupek

Dunstan

Cutler

et al. 2019

Preprint

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The transcriptomic and proteomic characterisation of CD4 + T cells at the single-cell level has been performed traditionally by two largely exclusive types of technologies: single cell RNAsequencing (scRNA-seq) technologies and antibody-based cytometry. Here we demonstrate that the simultaneous targeted quantification of mRNA and protein expression in single-cells provides a high-resolution map of human primary CD4 + T cells, and reveals precise trajectories of Th1, Th17 and regulatory T-cell differentiation in blood and tissue. We report modest correlation between mRNA and protein in primary CD4 + T cells at the single-cell level, highlighting the value of protein expression data to characterise cell effector function. This transcriptomic and proteomic hybrid technology provides a massively-parallel, cost-effective, solution to dissect the heterogeneity of immune cell populations and to immunophenotype rare and potentially pathogenic immune subsets, and could have important clinical applications to redefine differentiation and activation of circulating and tissue-resident human immune cells.

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“…Transcription factor activity according to SCENIC analysis tracked the trend from Th1-like at day 9 (Runx2, Runx3, Prdm1) to TFH-like at day 30 (Lef1, Pou2af1) ( Fig. 4g) 32,33 . In addition, a consistent subset of genes associated with lung residency (Tnfrsf4, Vps37b, Fth1, Crem) was detected by differential expression analysis between lung and LN at each separate time point ( Supplementary Fig.…”

mentioning

confidence: 93%

Redefining CD4 T cell residency: Helper T cells orchestrate protective humoral immunity in the lung

Swarnalekha

Schreiner

Litzler

et al. 2020

Preprint

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Influenza is a severe and acute respiratory pathogen, and a significant cause for morbidity, particularly in young children and the elderly. Following influenza infection, clonally expanded T cells take up permanent residence in the lung where they are poised to rapidly respond to challenge infection. The non-circulating status of these tissue resident memory (TRM) cells makes them an attractive target for vaccination. While many studies have characterized CD8 TRM cells, less is known about the heterogeneity and protective capacity of CD4 TRM cells. Here we characterized the dynamics and transcriptional regulation of lung resident CD4 T cells to define a nonlymphoid signature that removes the bias created by the prevalence of Th1 helper cells during viral infection. We identified a novel population of long-lived T resident helper (TRH) cells that requires intrinsic Bcl6 expression for their differentiation. Although TRH cells also depend on B cells, they are generated independently of T follicular helper effector cells in the lymph node. In contrast to lung resident Th1 cells, TRH cells are tightly co-localized with B cells in inducible Bronchus Associated Lymphoid Tissue (iBALT). Deletion of Bcl6 in CD4 T cells prior to heterotypic challenge infection results in redistribution of CD4 T cells outside of iBALT areas and impaired local antibody production. These data highlight lung iBALT as a niche for the homeostasis and survival of TRH cells, and further suggest that vaccination strategies to selectively induce TRH cells can improve protective immunity in the tissue.2 MainSeasonal influenza epidemics are a major cause of global morbidity and mortality. Although annually administered influenza vaccines are among the most widely used in the world, vaccine-elicited neutralizing antibodies offer poor protection against new influenza strains 1 . In contrast, there is evidence that prior influenza infection can accelerate viral clearance after heterotypic infection in both mice and humans 2,3,4,5,6 . Emerging data suggests that the targeted generation of CD4 memory T cells recognizing conserved epitopes from internal viral proteins may form the basis of a universal influenza virus vaccine 7,8 . CD4 memory T cells are induced following immunization or infection and can be recalled to generate secondary effectors during a challenge infection. Several subsets of CD4 memory cells have been described, including central memory (TCM) and effector memory (TEM) cells which circulate through secondary lymphoid and non-lymphoid tissues 9 . More recently, tissue resident memory (TRM) cells that persist in barrier tissues such as lung and skin have been described 10 . Although CD4 T cells actually outnumber CD8 T cells in barrier tissues, the majority of studies have focused on the requirements for CD8 TRM cell differentiation. In addition, although CD4 T cells are renowned for their substantial plasticity during immune responses, less is known about diversification within the CD4 TRM cell compartment 11,12,13,14,15,16 .Influenza i...

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The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6

Cited by 42 publications

References 77 publications

Bach2 Controls T Follicular Helper Cells by Direct Repression of Bcl-6

Bach2 Controls T Follicular Helper Cells by Direct Repression of Bcl-6

Discovery of CD80 and CD86 as recent activation markers on regulatory T cells by protein-RNA single-cell analysis

Redefining CD4 T cell residency: Helper T cells orchestrate protective humoral immunity in the lung

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