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ICOS-expressing Treg cells influence the composition of anti-tumor CTL population

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE226471 | GEO | 2024/07/18

REPOSITORIES: GEO

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ICOS-deficient Treg cells can prevent spontaneous autoimmunity but are impaired in controlling acute inflammation

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

ICOS costimulation is indispensable for the differentiation of T follicular regulatory cells

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

Engagement of ICOS in tissues promotes establishment of CD8+ tissue-resident memory T cells

Project description:Recirculating and tissue-resident memory CD8+ T cells provide distinct modes of immune protection, yet the signals that dictate differentiation of these populations are ill-defined. In particular, the interactions within tissues that promote generation of resident memory T cells (TRM) are unclear. Here, we show that the inducible costimulatory molecule ICOS, well known to regulate differentiation of CD4+ T cell populations, is required for CD8+ TRM but not recirculating memory subsets. Furthermore, ICOS engagement during CD8+ T cell recruitment to non-lymphoid tissues is critical for efficient TRM establishment: ICOS/ICOS-L interactions are dispensable throughout CD8+ T cell priming and for TRM maintenance, while ICOS-L expression by radioresistant cells is key for optimal TRM generation. This role for ICOS depends on its ability to signal through PI3K. Together, our data illustrate that specific local costimulatory cues promote production of tissue-resident populations, with potential implication for therapeutic manipulation.

2021-12-20 | GSE185342 | GEO

Gene expression comparison between the murine T-cell hybridoma 6-13-64 ICOS(-) population and ICOS(+) population

Project description:ICOS (Inducible Costimulator) is a T cell costimulatory molecule. We found that the cloned T-cell hybridoma 6-13-64 consists of two populations, ICOS expressing and non-expressing. The aim of this study is to screen for candidate genes that regulate ICOS gene expression by transcriptional profiling and comparison of the ICOS-positive and ICOS-negative subpopulations isolated from the 6-13-64 T-cell hybridoma. One-condition experiment, ICOS(-) vs. ICOS(+) cells. Independently grown and harvested. One replicate per array.

2012-03-31 | E-GEOD-20922 | biostudies-arrayexpress

Gene expression comparison between the murine T-cell hybridoma 6-13-64 ICOS(-) population and ICOS(+) population

2012-04-01 | GSE20922 | GEO

ICOS-expressing Treg cells influence the composition of anti-tumor CTL population

Project description:ICOS-expressing Treg cells influence the composition of anti-tumor CTL population

| PRJNA940394 | ENA

Single cell RNA sequencing of paired non small cell lung carcinoma tissue and peripheral blood from 5 donors

Project description:The immunosuppressive tumour microenvironment constitutes a significant hurdle to immune checkpoint inhibitors response. Both soluble factors and specialised immune cells such as regulatory T cells (TReg) are key components of active intratumoural immunosuppression. Previous studies have shown that Inducible Co-Stimulatory receptor (ICOS) can be highly expressed in the tumour microenvironment, especially on immunosuppressive TReg, suggesting that it represents a relevant target for preferential depletion of these cells. Here, we performed immune profiling of samples from paired tumour and peripheral blood of 5 patients with non-small cell lung cancer (NSCLC). We found Icos mRNA expression in NSCLC samples was higher in TRegs than in other T cell subsets and higher in the TME than in the periphery with the expression pattern in both compartments following the general trend of: TReg > CD4non-TReg > CD8 > Other.

2020-09-01 | E-MTAB-9451 | biostudies-arrayexpress

Spatial transcriptome analysis of muscle sections from Icos-/- NOD mice with established myositis

Project description:Icos-/- NOD mice are a model of spontaneous myositis. By using Nanostring GeoMx technology (Mouse WTA), we aimed to investigate the differences in gene expression between myofibers of Icos+/+ NOD (WT) mice and myofibers from Icos-/- NOD mice either in direct contact or not with large infiltrate clusters.

2024-05-29 | GSE262352 | GEO

ICOS-mediated inactivation of the FOXO1 transcription factor in the differentiation of T follicular helper cells

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

Role of ICOS:ICOSL interaction in acute GVHD

Project description:Inducible co-stimulator (ICOS) interaction with its ligand (ICOSL) is involved in several T cell effector functions. While blockade of ICOS:ICOSL interaction in chronic graft versus host disease (GVHD) seems benefi cial, results for acute GVHD remain controversial. To further elucidate its role in acute GVHD, C57BL / 6 mice were lethally irradiated and reconstituted with allogeneic spleen cells in the absence or presence of ICOSL-blocking mAb. Mice reconstituted with allogeneic spleen cells experienced severe GVHD and died untreated within 6 – 9 days after transplantation. Mice treated with an anti-ICOSL mAb starting from day 3 after transplantation gained weight again and survived for at least additional 12 days, although the treatment was already stopped at day 11 after transplantation. In contrast, the anti-ICOSL treatment starting from day 0 did not prevent GVHD. The diff erence between therapeutic (day 3) and prophylactic (day 0) anti-ICOSL treatment was independent of CD25 + CD4 + regulatory T cells since their depletion did not abrogate the therapeutic eff ect of ICOSL blockade. Microarray analysis revealed IFN- γ and chemokine up-regulation in spleen cells of prophylactically treated mice, emphasizing kinetic dependence of acute GVHD modulation via blockade of ICOS:ICOSL interaction.

2009-09-14 | GSE17995 | GEO

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