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Specific transcriptional programs differentiate ICOS and CD28 co-stimulatory signals in human naïve CD4 + T cells

ABSTRACT: a global transcriptome profiling was performed by RNA-seq on naïve CD4+ T cells upon ICOS or CD28 co-stimulation and bioinformatically was revealed a set of pathways specifically associated to each costimulatory molecule.

ORGANISM(S): Homo sapiens

PROVIDER: GSE191040 | GEO | 2022/08/11

REPOSITORIES: GEO

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Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability

Project description:Chimeric antigen receptor–T (CAR-T) cell therapies can eliminate relapsed and refractory tumors, but the durability of antitumor activity requires in vivo persistence. Differential signaling through the CAR costimulatory domain can alter the T cell metabolism, memory differentiation, and influence long-term persistence. CAR-T cells costimulated with 4-1BB or ICOS persist in xenograft models but those constructed with CD28 exhibit rapid clearance. Here, we show that a single amino acid residue in CD28 drove T cell exhaustion and hindered the persistence of CD28-based CAR-T cells and changing this asparagine to phenylalanine (CD28-YMFM) promoted durable antitumor control. In addition, CD28-YMFM CAR-T cells exhibited reduced T cell differentiation and exhaustion as well as increased skewing toward Th17 cells. Reciprocal modification of ICOS-containing CAR-T cells abolished in vivo persistence and antitumor activity. This finding suggests modifications to the costimulatory domains of CAR-T cells can enable longer persistence and thereby improve antitumor response.

2020-02-11 | GSE145007 | 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

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

Transcriptional signature of Th17 cells expressing ICOS-based CARs

2014-06-26 | GSE58867 | 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

Transcriptional signature of Th17 cells expressing ICOS-based CARs

Project description:Analysis of TH17 cells redirected with chimeric antigen receptors (CAR) expressing various signaling domains (including CD28, 4-1BB and ICOS) after surrogate antigen stimulation. Our results showed that T cells redirected with an ICOS-based CAR specifically retained a genotype of TH17 cells with expression of Il17a, Il17f, Il1r1, Ccl20, Rorc, and in the absence of Foxp3 CAR-redirected TH17 cells from three different human normal donors were stimulated with immobilized recombinant mesothelin. Gene expression levels were determined prior to stimulation (day 0) and 4, 8, 24 and 96 hours upon antigen recognition.

2014-06-26 | E-GEOD-58867 | biostudies-arrayexpress

Gene expression in self-activating CAR-T cells with CD28 or 4-1BB costimulatory domains.

Project description:We observed self-activation of SKM-CAR-T cells which target novel mesothelioma antigen. CAR-T with CD28 costimulatory domain showed signs of exhaustion while those with 4-1BB costimulatory domain did not. Changes in the gene expression by substituting CD28 co-stimulatory domain to 4-1BB co-stimulatory domain was investigated.

2023-05-28 | GSE231443 | GEO

T cell Co-Stimulatory molecules ICOS and CD28 stratify idiopathic pulmonary fibrosis survival.

Project description: Not available

| S-EPMC7243672 | biostudies-literature

Impaired T-cell function in patients with novel ICOS

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

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