Dataset Information

Increased IL-2 and Reduced TGF-β Upon T-Cell Stimulation are Associated with GM-CSF Upregulation in Multiple Immune Cell Types in Multiple Sclerosis.

ABSTRACT: Granulocyte macrophage colony stimulating factor (GM-CSF) is a pro-inflammatory cytokine produced by immune cells. Recent evidence suggests that GM-CSF plays an important role in multiple sclerosis (MS) pathogenesis. We investigated the expression and regulation of GM-CSF in different immune cells in MS. We also investigated the differentiation and frequency of GM-CSF-producing Th cells that do not co-express interferon (IFN)-γ or interleukin-17 (IL-17) (Th-GM cells) in MS. We found a significant increase in the percentage of GM-CSF-expressing Th cells, Th1 cells, Th-GM cells, cytotoxic T (Tc) cells, monocytes, natural killer (NK) cells, and B cells in PBMC from MS patients stimulated with T cell stimuli. Stimulated PBMC culture supernatants from MS patients contained significantly higher levels of IL-2, IL-12, IL-1β, and GM-CSF and significantly lower levels of transforming growth factor (TGF-)β. Blocking IL-2 reduced the frequency of Th-GM cells in PBMC from MS patients. The frequency of Th-GM cells differentiated in vitro from naïve CD4+ T cells was significantly higher in MS patients and was further increased in MS with IL-2 stimulation. These findings suggest that all main immune cell subsets produce more GM-CSF in MS after in vitro stimulation, which is associated with defective TGF-β and increased IL-2 and IL-12 production. Th-GM cells are increased in MS. GM-CSF may be a potential therapeutic target in MS.

SUBMITTER: Aram J

PROVIDER: S-EPMC7400438 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Increased IL-2 and Reduced TGF-β Upon T-Cell Stimulation are Associated with GM-CSF Upregulation in Multiple Immune Cell Types in Multiple Sclerosis.

Aram Jehan J Frakich Nanci N Morandi Elena E Alrouji Mohammed M Samaraweera Amal A Onion David D Spendlove Ian I Colombo Sergio L SL Tanasescu Radu R Gran Bruno B Constantinescu Cris S CS

Biomedicines 20200718 7

Granulocyte macrophage colony stimulating factor (GM-CSF) is a pro-inflammatory cytokine produced by immune cells. Recent evidence suggests that GM-CSF plays an important role in multiple sclerosis (MS) pathogenesis. We investigated the expression and regulation of GM-CSF in different immune cells in MS. We also investigated the differentiation and frequency of GM-CSF-producing Th cells that do not co-express interferon (IFN)-γ or interleukin-17 (IL-17) (Th-GM cells) in MS. We found a significan ...[more]

PMID: 32708498

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Project description:Conventional type 1 dendritic cells (cDC1) and conventional type 2 dendritic cells (cDC2) have attracted increasing attention as alternatives to monocyte-derived dendritic cells (moDCs) in cancer immunotherapy. Use of cDCs for therapy has been hindered by their low numbers in peripheral blood. In the present study, we found that extensive spontaneous apoptosis and cDC death in culture within 24hrs represent an additional challenge. Different media conditions that maintain cDC viability and function were investigated. CD141+ cDC1 and CD1c+ cDC2 were isolated from healthy blood donor buffy coats. Low viabilities were found with CellGenix DC, RPMI-1640, and X-VIVO 15 standard culture media and with several supplements at 24hrs and 48hrs. Among multiple factors it was found that GM-CSF improved both cDC1 and cDC2 viability, whereas Flt3-L and IL-4 only increased viability of cDC1 and cDC2, respectively. Combinations of these three cytokines improved viability of both cDCs further, both at 24hrs and 48hrs time points. Although these cytokines have been extensively investigated for their role in myeloid cell differentiation, and are also used clinically, their effects on mature cDCs remain incompletely known, in particular effects on pro-inflammatory or tolerogenic cDC features. HLA-DR, CD80, CD83, CD86, PD-L1 and PD-L2 cDC membrane expressions were relatively little affected by GM-CSF, IL-4 and Flt3-L cytokine supplements compared to the strong induction following Toll-like receptor (TLR) stimulation for 24hrs. With minor exceptions the three cytokines appeared to be permissive to the TLR-induced marker expression. Allogeneic mixed leukocyte reaction showed that the cytokines promoted T-cell proliferation and revealed a potential to boost both Th1 and Th2 polarizing cytokines. GM-CSF and Flt3-L and their combination improved the capability of cDC1 for dextran uptake, while in cDC2, dextran capture was improved by GM-CSF. The data suggest that GM-CSF, IL-4 and Flt3-L and combinations might be beneficial for DC viability and function in vitro. Limited viability of cDCs could be a confounding variable experimentally and in immunotherapy.

Project description:IntroductionEndogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of myeloid cells, is now known to support maturation and maintain the metabolic capacity of mononuclear phagocytes including monocytes, macrophages, and dendritic cells. These cells sense and attack potential pathogens, present antigens to adaptive immune cells, and recruit other immune cells. Recombinant human (rhu) GM-CSF (e.g., sargramostim [glycosylated, yeast-derived rhu GM-CSF]) has immune modulating properties and can restore the normal function of mononuclear phagocytes rendered dysfunctional by deficient or insufficient endogenous GM-CSF.MethodsWe reviewed the emerging biologic and cellular effects of GM-CSF. Experts in clinical disease areas caused by deficient or insufficient endogenous GM-CSF examined the role of GM-CSF in mononuclear phagocyte disorders including autoimmune pulmonary alveolar proteinosis (aPAP), diverse infections (including COVID-19), wound healing, and anti-cancer immune checkpoint inhibitor therapy.ResultsWe discuss emerging data for GM-CSF biology including the positive effects on mitochondrial function and cell metabolism, augmentation of phagocytosis and efferocytosis, and immune cell modulation. We further address how giving exogenous rhu GM-CSF may control or treat mononuclear phagocyte dysfunction disorders caused or exacerbated by GM-CSF deficiency or insufficiency. We discuss how rhu GM-CSF may augment the anti-cancer effects of immune checkpoint inhibitor immunotherapy as well as ameliorate immune-related adverse events.DiscussionWe identify research gaps, opportunities, and the concept that rhu GM-CSF, by supporting and restoring the metabolic capacity and function of mononuclear phagocytes, can have significant therapeutic effects. rhu GM-CSF (e.g., sargramostim) might ameliorate multiple diseases of GM-CSF deficiency or insufficiency and address a high unmet medical need.

Dataset Information

Increased IL-2 and Reduced TGF-β Upon T-Cell Stimulation are Associated with GM-CSF Upregulation in Multiple Immune Cell Types in Multiple Sclerosis.

Publications

Increased IL-2 and Reduced TGF-β Upon T-Cell Stimulation are Associated with GM-CSF Upregulation in Multiple Immune Cell Types in Multiple Sclerosis.

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