ICOS costimulation is indispensable for the differentiation of T follicular regulatory cells
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ABSTRACT:
PROVIDER: PRJNA692739 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13450800_1.fastq.gz | Fastqsanger.gz | |||
| SRR13450800_2.fastq.gz | Fastqsanger.gz | |||
| SRR13450799_1.fastq.gz | Fastqsanger.gz | |||
| SRR13450799_2.fastq.gz | Fastqsanger.gz |
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Project description:ICOS is a T cell costimulatory receptor critical for Tfh cell generation and function. However, the role of ICOS in Tfr cell differentiation remains unclear. Using Foxp3-Cre-mediated ICOS knockout (ICOS FC) mice, we show that ICOS deficiency in Treg-lineage cells drastically reduces the number of Tfr cells during GC reactions but has a minimal impact on conventional Treg cells. Single-cell transcriptome analysis of Foxp3+ cells at an early stage of the GC reaction suggests that ICOS normally inhibits Klf2 expression to promote follicular features including Bcl6 upregulation. Further, ICOS costimulation promotes nuclear localization of NFAT2, a known driver of CXCR5 expression. Notably, ICOS FC mice had an unaltered overall GC B cell output but showed signs of expanded autoreactive B cells along with elevated autoantibody titers. Thus, our study demonstrates that ICOS costimulation is critical for Tfr cell differentiation and highlights the importance of Tfr cells in maintaining humoral immune tolerance during GC reactions.
2023-02-02 | GSE164995 | GEO
Project description:ICOS is a T-cell costimulatory receptor critical for Tfh cell generation and function. However, the role of ICOS in Tfr cell differentiation remains unclear. Using Foxp3-Cre-mediated ICOS knockout (ICOS FC) mice, we show that ICOS deficiency in Treg-lineage cells drastically reduces the number of Tfr cells during GC reactions but has a minimal impact on conventional Treg cells. Single-cell transcriptome analysis of Foxp3+ cells at an early stage of the GC reaction suggests that ICOS normally inhibits Klf2 expression to promote follicular features including Bcl6 up-regulation. Furthermore, ICOS costimulation promotes nuclear localization of NFAT2, a known driver of CXCR5 expression. Notably, ICOS FC mice had an unaltered overall GC B-cell output but showed signs of expanded autoreactive B cells along with elevated autoantibody titers. Thus, our study demonstrates that ICOS costimulation is critical for Tfr cell differentiation and highlights the importance of Tfr cells in maintaining humoral immune tolerance during GC reactions.
| S-EPMC9909462 | biostudies-literature
Project description:T follicular helper (Tfh) cells constitute an essential cell type in the induction of antibodies. We report that CD4 T cells lacking Foxo1 almost uniformly became CXCR5int Tfh cells following immunization. Moreover, a Foxo1 loss-of-function complemented an Icos mutation allowing the appearance of Tfh cells along with follicular, class-switched B cells and IgG isotype anti-DNA antibodies. Similarly, FOXO1 deficient Tfh differentiation displayed a substantially reduced dependence on ICOSL. Functional and molecular analyses show that FOXO1 regulates Tfh differentiation through a broad program of gene expression exemplified by positive regulation of Icos and negative regulation of Bcl6. These results demonstrate that a key step in Tfh differentiation is the ICOS-initiated activation of the PI3K-AKT pathway resulting in the inactivation of FOXO1. Performed ChIP-seq analysis to examine the role of foxo1 in the development of Tfh cells
2013-06-01 | E-GEOD-46525 | biostudies-arrayexpress
Project description:T follicular helper (Tfh) cells are essential in the induction of high-affinity, class-switched antibodies. The differentiation of Tfh cells is a multi-step process that depends upon the co-receptor ICOS and the activation of phosphoinositide-3 kinase leading to the expression of key Tfh cell genes. We report that ICOS signaling inactivates the transcription factor FOXO1, and a Foxo1 genetic deletion allowed for generation of Tfh cells with reduced dependence on ICOS ligand. Conversely, enforced nuclear localization of FOXO1 inhibited Tfh cell development even though ICOS was overexpressed. FOXO1 regulated Tfh cell differentiation through a broad program of gene expression exemplified by its negative regulation of Bcl6. Final differentiation to germinal center Tfh cells (GC-Tfh) was instead FOXO1 dependent as the Foxo1(-/-) GC-Tfh cell population was substantially reduced. We propose that ICOS signaling transiently inactivates FOXO1 to initiate a Tfh cell contingency that is completed in a FOXO1-dependent manner.
2015-01-01 | GSE46525 | GEO
Project description:The maintenance of the TFH phenotype depends on continuous signals via ICOS. For a global assessment of differences in gene expression after interruption of the ICOS pathway a genome wide transcriptome analysis was performed. We used the OT-II adoptive transfer system to isolate antigen-specific TFH cells (day 6 after immunization) after short-term (6 hours) blockade of the ICOS pathway using a monoclonal antibody against ICOS-L. Gene expression profiles of TFH cells with or without ICOS-L blockade. Affymetrix MG 430 2.0 whole genome arrays were performed in duplicates for the control and blockade group (4 arrays in total). To obtain genes significantly regulated upon ICOS L blockade, the expression profiles of TFH cells treated with an isotype control or anti-ICOS-L antibody were compared to each other. After total RNA extraction, reverse transcription, cDNA extraction, the biotinylated cRNA was transcribed, fragmented, and 15 M-BM-5g cRNA hybridized in duplicates for each of the two groups to the 4 GeneChip arrays: Group1 TFH cells control, Group2 TFH cells ICOS-L blockade.
2015-01-19 | E-GEOD-49314 | biostudies-arrayexpress
Project description:The maintenance of the TFH phenotype depends on continuous signals via ICOS. For a global assessment of differences in gene expression after interruption of the ICOS pathway a genome wide transcriptome analysis was performed. We used the OT-II adoptive transfer system to isolate antigen-specific TFH cells (day 6 after immunization) after short-term (6 hours) blockade of the ICOS pathway using a monoclonal antibody against ICOS-L.
2015-01-19 | GSE49314 | GEO
Project description:The role of ICOS in anti-tumor T cell responses and overall tumor progression has been controversial. Here, we compared tumor progression in mice lacking ICOS only in Treg cells or in all T cells. We found that Treg-specific ICOS knockout reduces the overall tumor burden compared to Cre control mice with increased T effector/Treg ratios in the tumor. In contrast, there was no difference in the tumor burden in mice lacking ICOS in all the T cell compartments. This suggests a dual role of ICOS costimulation in promoting pro- and anti-tumor T cell responses. Consistent with reduced tumor burden, we found that Treg-specific deletion of ICOS leads to an increase of CD8+ CTLs that express high levels of granzyme B and perforin. Moreover, single-cell transcriptome analysis revealed an increase of Ly108hiEomeshi CD8+ T cell subset at the cost of Ly108hiT-bethi subset in Treg-specific knockout mice. These results suggest that ICOS-expressing Treg cells suppress CTL maturation process at the level of Eomes upregulation, a critical step known to drive perforin expression and cytotoxicity. Collectively, our data imply that cancer immunotherapies using ICOS agonist antibodies would work better in Treg-low tumors or when they are combined with regimens that deplete tumor-infiltrating Treg cells.
2024-07-18 | GSE226471 | GEO
Project description:During persistent antigen stimulation, PD-1+CD8 T cells are maintained by progenitor exhausted PD-1+TCF-1+CD8 T cells (Tpex). Tpex respond to PD-1 blockade, and regulation of Tpex differentiation into more functional Tex is of major interest for cancer immunotherapies. Tpex express high levels of Inducible Costimulator (ICOS), but the role of ICOS for PD-1+CD8 T cell responses has not been addressed. In chronic infection, ICOS-deficiency increased both number and quality of virus-specific CD8 T cells, with accumulation of effector-like Tex due to enhanced survival. Mechanistically, loss of ICOS signaling potentiated FoxO1 activity and memory features of Tpex. ICOS-deficient Tex displayed enhanced survival and improved cytokine production. In chronically-infected mice, ICOS-Ligand blockade expanded effector-like Tex, reduced viral load and potentiated anti-PD-L1 therapy. In a mouse model of hepatocellular carcinoma, ICOS inhibition improved cytokine production by tumor-specific PD-1+CD8 T cells and sensitized tumors to PD-1 targeted therapy. Overall, we show that sustained ICOS costimulation limits CD8 T cell responses during chronic antigen exposure.
2025-07-07 | GSE288889 | GEO
Project description:ICOS is induced in activated T cells and its main role is to boost differentiation and function of effector T cells. ICOS is also constitutively expressed in a subpopulation of Foxp3+ regulatory T cells under steady-state condition. Studies using ICOS germline knockout mice or ICOS-blocking reagents suggested that ICOS has supportive roles in regulatory T (Treg) cell homeostasis, migration, and function. To avoid any compounding effects that may arise from ICOS-deficient non-Treg cells, we generated a conditional knockout system in which ICOS expression is selectively abrogated in Foxp3-expressing cells (ICOS FC mice). Compared to Foxp3-Cre control mice, ICOS FC mice showed a minor numerical deficit of steady-state Treg cells but did not show any signs of spontaneous autoimmunity, indicating that tissue-protective Treg populations do not heavily rely on ICOS costimulation. However, ICOS FC mice showed more severe inflammation in oxazolone-induced contact hypersensitivity, a model of atopic dermatitis. This correlated with elevated numbers of inflammatory T cells expressing IFN-γ and/or TNF-α in ICOS FC mice compared with the control group. In contrast, elimination of ICOS in all T cell compartments negated the differences, confirming that ICOS has a dual positive role in effector and Treg cells. Single-cell transcriptome analysis suggested that ICOS-deficient Treg cells fail to mature into T-bet+CXCR3+ “Th1-Treg” cells in the draining lymph node. Our results suggest that regimens that preferentially stimulate ICOS pathways in Treg cells might be beneficial for the treatment of Th1-driven inflammation.
2022-07-08 | GSE185254 | GEO
Project description:Interaction of ICOS - ICOS ligand is required for the germinal center formation, T-cell immune responses, and development of autoimmune diseases. Human ICOS deficiency with the identical ICOS mutation has been identified in nine patients worldwide. In vitro studies showed T-cell defect of the patients was mild, and in vivo autoimmunity was uncommon and mild. Here we report in-depth analysis of T-cell function in two siblings with novel ICOS deficiency. While the brother displayed mild skin infections, psoriasis-like skin region, and defective immunoglobulin class switching, the sister had more severe symptoms, which included immunodeficiency, rheumatoid arthritis, inflammatory bowel disease, interstitial pneumonitis, and psoriasis. Despite of normal CD3/CD28-induced proliferation and IL-2 production in vitro, peripheral blood T-cells from both patients demonstrated decreased percentage of CD4 central and effector memory T-cells and impaired production of Th1, Th2, and Th17 cytokines upon CD3/CD28 costimulation or upon PMA/ionophore stimulation. The defective polarization into effector cells were associated with impaired induction of T-bet, GATA3 and MAF and RORC. Reduced CTLA-4+CD45RO+ FoxP3+ regulatory T-cells and diminished induction of inhibitory cell surface molecules including CTLA-4 were also observed in the patients. Further analysis of the gene expression and immune functions of the patients demonstrated increased induction of RANKL, lack of IFN-g response, and loss of Itch expression upon activation in the female case with autoimmunity. Our study suggests extensive T-cell dysfunction and loss of balance between effector cells and regulatory cells in the ICOS-deficient patients may account for their immunodeficiency and/or autoimmune disorder.
2008-09-26 | GSE12875 | GEO