CTLA-4 Mediates Inhibitory Function of Mesenchymal Stem/Stromal Cells

Gaber, Timo; Schönbeck, K; Hoff, Holger; Tran, Cam Loan; Strehl, Cindy; Lang, Annemarie; Ohrndorf, Sarah; Pfeiffenberger, Moritz; Röhner, Eric; Matziolis, Georg; Burmester, G.-R.; Buttgereit, Frank; Hoff, Paula

doi:10.3390/ijms19082312

Cited by 39 publications

(33 citation statements)

References 50 publications

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“…We found that after four days of culture, the expression of CTLA-4 in T-cells of co-cultures with MSCs from all four sources significantly increased, coinciding with the decrease in T-cell proliferation; this suggests the participation of CTLA-4 + Tregs for this inhibition to occur. These observations are consistent with previous research, showing that BM-MSCs, UCB-MSCs, and PL-MSCs have immunosuppressive capacities by increasing CTLA-4 in co-cultures with CD3 + [18,48].…”

Section: Discussionsupporting

confidence: 93%

Mesenchymal Stem/Stromal Cells Derived from Dental Tissues: A Comparative In Vitro Evaluation of Their Immunoregulatory Properties Against T cells

Rosa-Ruiz

Álvarez-Pérez

Cortés-Morales

et al. 2019

Cells

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Bone marrow mesenchymal stem/stromal cells (BM-MSCs) have immunoregulatory properties and have been used as immune regulators for the treatment of graft-versus-host disease (GVHD). Human dental tissue mesenchymal stem cells (DT-MSCs) constitute an attractive alternative to BM-MSCs for potential clinical applications because of their accessibility and easy preparation. The aim of this in vitro study was to compare MSCs from dental pulp (DP-MSCs), gingival tissue (G-MSCs), and periodontal ligament (PDL-MSCs) in terms of their immunosuppressive properties against lymphoid cell populations enriched for CD3+ T cells to determine which MSCs would be the most appropriate for in vivo immunoregulatory applications. BM-MSCs were included as the gold standard. Our results demonstrated, in vitro, that MSCs from DP, G, and PDL showed immunoregulatory properties similar to those from BM, in terms of the cellular proliferation inhibition of both CD4+- and CD8+-activated T-cells. This reduced proliferation in cell co-cultures correlated with the production of interferon-γ and tumor necrosis factor alpha (TNF-α) and the upregulation of programmed death ligand 1 (PD-L1) in MSCs and cytotoxic T-cell-associated Ag-4 (CTLA-4) in T-cells and increased interleukin-10 and prostaglandin E2 production. Interestingly, we observed differences in the production of cytokines and surface and secreted molecules that may participate in T-cell immunosuppression in co-cultures in the presence of DT-MSCs compared with BM-MSCs. Importantly, MSCs from four sources favored the generation of T-cell subsets displaying the regulatory phenotypes CD4+CD25+Foxp3+ and CD4+CD25+CTLA-4+. Our results in vitro indicate that, in addition to BM-MSCs, MSCs from all of the dental sources analyzed in this study might be candidates for future therapeutic applications.

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Section: Discussionsupporting

confidence: 93%

Mesenchymal Stem/Stromal Cells Derived from Dental Tissues: A Comparative In Vitro Evaluation of Their Immunoregulatory Properties Against T cells

Rosa-Ruiz

Álvarez-Pérez

Cortés-Morales

et al. 2019

Cells

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“…As such, investigations into the expression pattern and function of CTLA-4 in non-tumor and nonhematopoietic tissue is warranted. In this regard, CTLA-4 expression has been reported in mesenchymal stem cells and placental fibroblasts (102,103) as well as the aforementioned normal melanocytes. Additionally, stimulation of cultured muscle cells with IL-1a IFN-g or IL-2 + anti-CD28 promoted CTLA-4 expression (104).…”

Section: Non-hematopoietic/non-cancermentioning

confidence: 95%

“…MSC CTLA-4 was determined to inhibit TNFa production by PHA-activated PBMCs, a phenomenon that was boosted by hypoxic conditions. Accordingly, hypoxic culture conditions significantly upregulated the expression of flCTLA-4 and sCTLA-4 in MSCs (103). Efforts to define the immunosuppressive landscape of the maternal-fetal landscape during pregnancy led to the discovery that fetal cells expressed CTLA-4 during gestation.…”

Section: Non-hematopoietic/non-cancermentioning

confidence: 99%

Beyond T-Cells: Functional Characterization of CTLA-4 Expression in Immune and Non-Immune Cell Types

et al. 2020

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The immune response consists of a finely-tuned program, the activation of which must be coupled with inhibitory mechanisms whenever initiated. This ensures tight control of beneficial anti-pathogen and anti-tumor responses while preserving tissue integrity, promoting tissue repair, and safeguarding against autoimmunity. A cogent example of this binary response is in the mobilization of co-stimulatory and co-inhibitory signaling in regulating the strength and type of a T-cell response. Of particular importance is the costimulatory molecule CD28 which is countered by CTLA-4. While the role of CD28 in the immune response has been thoroughly elucidated, many aspects of CTLA-4 biology remain controversial. The expression of CD28 is largely constrained to constitutive expression in T-cells and as such, teasing out its function has been somewhat simplified by a limited and specific expression profile. The expression of CTLA-4, on the other hand, while reported predominantly in T-cells, has also been described on a diverse repertoire of cells within both lymphoid and myeloid lineages as well as on the surface of tumors. Nonetheless, the function of CTLA-4 has been mostly described within the context of T-cell biology. The focus on T-cell biology may be a direct result of the high degree of amino acid sequence homology and the co-expression pattern of CD28 and CTLA-4, which initially led to the discovery of CTLA-4 as a counter receptor to CD28 (for which a T-cell-activating role had already been described). Furthermore, observations of the outsized role of CTLA-4 in Treg-mediated immune suppression and the striking phenotype of T-cell hyperproliferation and resultant disease in CTLA-4−/− mice contribute to an appropriate T-cell-centric focus in the study of CTLA-4. Complete elucidation of CTLA-4 biology, however, may require a more nuanced understanding of its role in a context other than that of T-cells. This makes particular sense in light of the remarkable, yet limited utility of anti-CTLA-4 antibodies in the treatment of cancers and of CTLA-4-Ig in autoimmune disorders like rheumatoid arthritis. By fully deducing the biology of CTLA-4-regulated immune homeostasis, bottlenecks that hinder the widespread applicability of CTLA-4-based immunotherapies can be resolved.

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“…In parallel, AKT activation paths are inhibited by the soluble PD-L1 and PD-L2 secreted by MSCs, so T cell activation and proliferation are inhibited [ 118 ]. Besides the T cell inhibition that is mediated by PD-1 and PD-L1, it was recently found that MSCs’ immunosuppressive performance is partly mediated through CTLA-4 that MSCs express several types of them [ 119 ].…”

Section: The Supportive Effects Of Mesenchymal Stem Cells On Tumor Grmentioning

confidence: 99%

Mesenchymal stem cells as a double-edged sword in tumor growth: focusing on MSC-derived cytokines

et al. 2021

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Mesenchymal stem cells (MSCs) show homing capacity towards tumor sites. Numerous reports indicate that they are involved in multiple tumor-promoting processes through several mechanisms, including immunosuppression; stimulation of angiogenesis; transition to cancer-associated fibroblasts; inhibition of cancer cell apoptosis; induction of epithelial–mesenchymal transition (EMT); and increase metastasis and chemoresistance. However, other studies have shown that MSCs suppress tumor growth by suppressing angiogenesis, incrementing inflammatory infiltration, apoptosis and cell cycle arrest, and inhibiting the AKT and Wnt signaling pathways. In this review, we discuss the supportive and suppressive impacts of MSCs on tumor progression and metastasis. We also discuss MSC-based therapeutic strategies for cancer based on their potential for homing to tumor sites.

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CTLA-4 Mediates Inhibitory Function of Mesenchymal Stem/Stromal Cells

Cited by 39 publications

References 50 publications

Mesenchymal Stem/Stromal Cells Derived from Dental Tissues: A Comparative In Vitro Evaluation of Their Immunoregulatory Properties Against T cells

Mesenchymal Stem/Stromal Cells Derived from Dental Tissues: A Comparative In Vitro Evaluation of Their Immunoregulatory Properties Against T cells

Beyond T-Cells: Functional Characterization of CTLA-4 Expression in Immune and Non-Immune Cell Types

Mesenchymal stem cells as a double-edged sword in tumor growth: focusing on MSC-derived cytokines

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