Opposing Development of Cytotoxic and Follicular Helper CD4 T Cells Controlled by the TCF-1-Bcl6 Nexus

Donnarumma, Tiziano; Young, George R.; Merkenschlager, Julia; Eksmond, Urszula; Bongard, Nadine; Nutt, Stephen L.; Boyer, Catherine; Dittmer, Ulf; Le‐Trilling, Vu Thuy Khanh; Trilling, Mirko; Bayer, Wibke; Kassiotis, George

doi:10.1016/j.celrep.2016.10.013

Cited by 49 publications

(75 citation statements)

References 45 publications

(101 reference statements)

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“…We also observed upregulation of Cd8a gene expression, although at very low expression levels (FPKM < 0.5) ( Figure 2C), correlating with the undetectable or low-level CD8α protein expression determined by flow cytometry ( Figure 1D). Moreover, in agreement with a study showing opposing development of CD4 + cytotoxic T cells and T follicular helper cells (18), BCL6 signatures were downregulated, and Blimp-1 (encoded by Prdm1) signatures ( Figure 2B) as well as Prdm1 expression ( Figure 2C) were upregulated. To obtain an understanding whether expression signatures in HDAC1 cKO -HDAC2 HET CD4 + T cells represent Th1-like or CTL lineage patterns, we performed gene set enrichment analyses (GSEAs).…”

Section: Resultssupporting

confidence: 91%

Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation

Preglej¹,

Hamminger²,

Luu³

et al. 2020

JCI Insight

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During the differentiation of naive CD4 + T cells into effector T cells, cell fate decisions into various Th subsets are made, and Th cell lineage-specific gene expression patterns are established and maintained. Epigenetic mechanisms, such as histone and DNA modifications, play a crucial role in these processes. Among these, modification of core histones by reversible lysine acetylation is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs), which are "classically" considered as transcriptional coactivators and corepressors, respectively. However, HDACs are also recruited to active gene loci and might, potentially with HATs, act context dependently as modulators of gene transcription. Moreover, many nonhistone targets have been emerging, and HATs/HDACs function beyond the epigenetic control of gene expression (10-12). To date, 18 members of the HDAC family (many of which are expressed in the T cell lineage) that are grouped into 4 classes have been identified (13). We have recently generated mice with a T cell-specific deletion of the class I histone deacetylases HDAC1 and HDAC2, which resulted in MHC class II-restricted CD4 + CD8αβ + T cells that, upon activation, initiate the upregulation of a Runx3/ CBFβ-dependent CD8 effector T cell-like program (14,15). This observation indicates that CD4 lineage insight.jci.org

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Section: Resultssupporting

confidence: 91%

Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation

Preglej¹,

Hamminger²,

Luu³

et al. 2020

JCI Insight

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“…However, it is also possible that CD4 þ CTLs may comprise a distinct, independent subset of CD4 þ effector T cells that differ from conventional Th1 cells (10). Indeed, several recent reports have identified specific markers for CD4 þ CTLs (11)(12)(13)(14). Interestingly, Eomes is expressed in many of the cells expressing these markers, as well as in other CD4 þ T cells with cytolytic properties (15)(16)(17)(18); these findings suggested that Eomes governs development of CD4 þ CTLs and that Eomes expression is a marker for CD4 þ CTLs.…”

mentioning

confidence: 99%

Role of T‐bet, the master regulator of Th1 cells, in the cytotoxicity of murine CD4⁺ T cells

Eshima

Misawa

Ohashi

et al. 2018

Microbiology and Immunology

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Although CD4 T cells are generally regarded as helper T cells, some activated CD4 T cells have cytotoxic properties. Given that CD4 cytotoxic T lymphocytes (CTLs) often secrete IFN-γ, CTL activity among CD4 T cells may be attributable to Th1 cells, where a T-box family molecule, T-bet serves as the "master regulator". However, although the essential contribution of T-bet to expression of IFN-γ has been well-documented, it remains unclear whether T-bet is involved in CD4 T cell-mediated cytotoxicity. In this study, to investigate the ability of T-bet to confer cytolytic activity on CD4 T cells, the T-bet gene (Tbx21) was introduced into non-cytocidal CD4 T cell lines and their cytolytic function analyzed. Up-regulation of FasL (CD178), which provided the transfectant with cytotoxicity, was observed in Tbx21transfected CD4 T cells but not in untransfected parental cells. In one cell line, T-bet transduction also induced perforin gene (Prf1) expression and Tbx21 transfectants efficiently killed Fas target cells. Although T-bet was found to repress up-regulation of CD40L (CD154), which controls FasL-mediated cytolysis, the extent of CD40L up-regulation on in vitro-differentiated Th1 cells was similar to that on Th2 cells, suggesting the existence of a compensatory mechanism. These results collectively indicate that T-bet may be involved in the expression of genes, such as FasL and Prf1, which confer cytotoxicity on Th1 cells.

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“…Tfh cells interact with B cells in the specialized areas of lymph nodes and spleens called germinal centers where the processes of somatic hypermutation and isotype switching occur. It has been shown that tumor infiltrating Tfh cells may help to maintain CTLs at tumor sites, though they do not differentiate into cells that produce cytotoxic granules [34–36]. Therefore, if the function of the bull’s eye synapse is solely the delivery of cytolytic granules, Tfh, like Th2 cells, may have a multifocal synapse structure.…”

Section: Discussionmentioning

confidence: 99%

Despite disorganized synapse structure, Th2 cells maintain directional delivery of CD40L to antigen-presenting B cells

Gardell

Parker

2017

PLoS ONE

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Upon recognition of peptide displayed on MHC molecules, Th1 and Th2 cells form distinct immunological synapse structures. Th1 cells have a bull’s eye synapse structure with TCR/ MHC-peptide interactions occurring central to a ring of adhesion molecules, while Th2 cells have a multifocal synapse with small clusters of TCR/MHC interactions throughout the area of T cell/antigen-presenting cell interaction. In this study, we investigated whether this structural difference in the immunological synapse affects delivery of T cell help. The immunological synapse is thought to ensure antigen-specific delivery of cytolytic granules and killing of target cells by NK cells and cytolytic T cells. In helper T cells, it has been proposed that the immunological synapse may direct delivery of other effector molecules including cytokines. CD40 ligand (CD40L) is a membrane-bound cytokine essential for antigen-specific T cell help for B cells in the antibody response. We incubated Th1 and Th2 cells overnight with a mixture of antigen-presenting and bystander B cells, and the delivery of CD40L to B cells and subsequent B cell responses were compared. Despite distinct immunological synapse structures, Th1 and Th2 cell do not differ in their ability to deliver CD40L and T cell help in an antigen-specific fashion, or in their susceptibility to inhibition of help by a blocking anti-CD40L antibody.

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Opposing Development of Cytotoxic and Follicular Helper CD4 T Cells Controlled by the TCF-1-Bcl6 Nexus

Cited by 49 publications

References 45 publications

Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation

Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation

Role of T‐bet, the master regulator of Th1 cells, in the cytotoxicity of murine CD4⁺ T cells

Despite disorganized synapse structure, Th2 cells maintain directional delivery of CD40L to antigen-presenting B cells

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Opposing Development of Cytotoxic and Follicular Helper CD4 T Cells Controlled by the TCF-1-Bcl6 Nexus

Cited by 49 publications

References 45 publications

Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation

Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation

Role of T‐bet, the master regulator of Th1 cells, in the cytotoxicity of murine CD4+ T cells

Despite disorganized synapse structure, Th2 cells maintain directional delivery of CD40L to antigen-presenting B cells

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Role of T‐bet, the master regulator of Th1 cells, in the cytotoxicity of murine CD4⁺ T cells