Current Understanding of Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) Signaling in T-Cell Biology and Disease Therapy

Kim, Gil-Ran; Choi, Je-Min

doi:10.14348/molcells.2022.2056

Cited by 30 publications

(18 citation statements)

References 89 publications

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“…Moreover, these patients had significantly higher expression of immune checkpoint proteins, including the inhibitory T‐cell receptor TIM3 (T cell immunoglobulin and mucin domain‐containing protein 3, also known as TIGIT), 33 and PD‐L2 (also known as PDCDILG2), an alternate ligand for PD‐1 that also inhibits T‐cell activation 34 (Figure 1D ). CTLA4, another inhibitory T‐cell receptor, 35 showed a trend toward increased expression in older patients compared to younger patients (Figure 1D ). Taken together, these results suggest that LUAD in patients >70 years displayed a more immunosuppressive TME compared to younger patients.…”

Section: Resultsmentioning

confidence: 99%

Identification of age‐ and immune‐related gene signatures for clinical outcome prediction in lung adenocarcinoma

et al. 2023

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BackgroundThe understanding of the factors causing decreased overall survival (OS) in older patients compared to younger patients in lung adenocarcinoma (LUAD) remains.MethodsGene expression profiles of LUAD were obtained from publicly available databases by Kaplan‐Meier analysis was performed to determine whether age was associated with patient OS. The immune cell composition in the tumor microenvironment (TME) was evaluated using CIBERSORT. The fraction of stromal and immune cells in tumor samples were also using assessed using multiple tools including ESTIMATE, EPIC, and TIMER. Differentially expressed genes (DEGs) from the RNA‐Seq data that were associated with age and immune cell composition were identified using the R package DEGseq. A 22‐gene signature composed of DEGs associated with age and immune cell composition that predicted OS were constructed using Least Absolute Shrinkage and Selection Operator (LASSO).ResultsIn The Cancer Genome Atlas (TCGA)‐LUAD dataset, we found that younger patients (≤70) had a significant better OS compared to older patients (>70). In addition, older patients had significantly higher expression of immune checkpoint proteins including inhibitory T cell receptors and their ligands. Moreover, analyses using multiple bioinformatics tools showed increased immune infiltration, including CD4+ T cells, in older patients compared to younger patients. We identified a panel of genes differentially expressed between patients >70 years compared to those ≤70 years, as well as between patients with high or low immune scores and selected 84 common genes to construct a prognostic gene signature. A risk score calculated based on 22 genes selected by LASSO predicted 1, 3, and 5‐year OS, with an area under the curve (AUC) of 0.72, 0.72, 0.69, receptively, in TCGA‐LUAD dataset and an independent validation dataset available from the European Genome‐phenome Archive (EGA).ConclusionOur results demonstrate that age contributes to OS of LUAD patients atleast in part through its association with immune infiltration in the TME.

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Section: Resultsmentioning

confidence: 99%

Identification of age‐ and immune‐related gene signatures for clinical outcome prediction in lung adenocarcinoma

et al. 2023

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“…CTLA-4 (CD152) is an immune checkpoint molecule that plays a crucial role in regulating T cell activity by competing with CD28 signaling to bind to the B7 molecules expressed on the surface of APCs ( 61 – 64 ). CTLA-4-Ig (Abatacept), a drug that combines the extracellular domain of CTLA-4 with the Fc region of an immunoglobulin, has been FDA-approved as a treatment for rheumatoid arthritis, active psoriatic arthritis.…”

Section: Discussionmentioning

confidence: 99%

Alleviating psoriatic skin inflammation through augmentation of Treg cells via CTLA-4 signaling peptide

Lee,

Nam,

Kim

et al. 2023

Front. Immunol.

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Psoriasis is a chronic inflammatory skin disease characterized by hyperplasia of keratinocytes and immune cell infiltration. The IL-17-producing T cells play a key role in psoriasis pathogenesis, while regulatory T (Treg) cells are diminished during psoriatic inflammation. Current psoriasis treatments largely focus on IL-17 and IL-23, however, few studies have explored therapeutic drugs targeting an increase of Treg cells to control immune homeostasis. In this study, we investigated the effects of a cytotoxic T lymphocyte antigen-4 (CTLA-4) signaling peptide (dNP2-ctCTLA-4) in Th17, Tc17, γδ T cells, Treg cells in vitro and a mouse model of psoriasis. Treatment with dNP2-ctCTLA-4 peptide showed a significant reduction of psoriatic skin inflammation with increased Treg cell proportion and reduced IL-17 production by T cells, indicating a potential role in modulating psoriatic skin disease. We compared dNP2-ctCTLA-4 with CTLA-4-Ig and found that only dNP2-ctCTLA-4 ameliorated the psoriasis progression, with increased Treg cells and inhibited IL-17 production from γδ T cells. In vitro experiments using a T cell-antigen presenting cell co-culture system demonstrated the distinct mechanisms of dNP2-ctCTLA-4 compared to CTLA-4-Ig in the induction of Treg cells. These findings highlight the therapeutic potential of dNP2-ctCTLA-4 peptide in psoriasis by augmenting Treg/Teff ratio, offering a new approach to modulating the disease.

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“…The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), the first inhibitory molecule discovered, is a member of the immunoglobulin superfamily and presents an inhibitory inducing immunologic response, having the ability to bind to both B7-1 and B7-2 [ 52 , 53 ]. It is similar in structure to CD28, as seen on T cells in a resting state, and may be expressed only after cell activation.…”

Section: Immunologic Strategies In Vcamentioning

confidence: 99%

Exploring Costimulatory Blockade-Based Immunologic Strategies in Transplantation: Are They a Promising Immunomodulatory Approach for Organ and Vascularized Composite Allotransplantation?

Grosu-Bularda,

Hodea,

Zamfirescu

et al. 2024

JPM

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The field of transplantation, including the specialized area of vascularized composite allotransplantation (VCA), has been transformed since the first hand transplant in 1998. The major challenge in VCA comes from the need for life-long immunosuppressive therapy due to its non-vital nature and a high rate of systemic complications. Ongoing research is focused on immunosuppressive therapeutic strategies to avoid toxicity and promote donor-specific tolerance. This includes studying the balance between tolerance and effector mechanisms in immune modulation, particularly the role of costimulatory signals in T lymphocyte activation. Costimulatory signals during T cell activation can have either stimulatory or inhibitory effects. Interfering with T cell activation through costimulation blockade strategies shows potential in avoiding rejection and prolonging the survival of transplanted organs. This review paper aims to summarize current data on the immunologic role of costimulatory blockade in the field of transplantation. It focuses on strategies that can be applied in vascularized composite allotransplantation, offering insights into novel methods for enhancing the success and safety of these procedures.

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Current Understanding of Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) Signaling in T-Cell Biology and Disease Therapy

Cited by 30 publications

References 89 publications

Identification of age‐ and immune‐related gene signatures for clinical outcome prediction in lung adenocarcinoma

Identification of age‐ and immune‐related gene signatures for clinical outcome prediction in lung adenocarcinoma

Alleviating psoriatic skin inflammation through augmentation of Treg cells via CTLA-4 signaling peptide

Exploring Costimulatory Blockade-Based Immunologic Strategies in Transplantation: Are They a Promising Immunomodulatory Approach for Organ and Vascularized Composite Allotransplantation?

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