Foxp3 expression in T regulatory cells and other cell lineages

Devaud, Christel; Darcy, Phillip K.; Kershaw, Michael H.

doi:10.1007/s00262-014-1581-4

Cited by 79 publications

(63 citation statements)

References 82 publications

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“…Using the Human Protein Atlas [15, 16], we first quantified expression of Foxp3, a bona fide marker for Tregs [18, 19], in primary tumors of several solid cancers using immunohistochemistry. We found that Foxp3 + Tregs were detected in human pancreatic cancer at a frequency comparable to colorectal and lung cancers and higher than that seen in melanoma and prostate cancer (Fig.…”

Section: Resultsmentioning

confidence: 99%

CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer

Bengsch

Knoblock

Liu

et al. 2017

Cancer Immunol Immunother

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The ability of some tumors to exclude effector T cells represents a major challenge to immunotherapy. T cell exclusion is particularly evident in pancreatic ductal adenocarcinoma (PDAC), a disease where blockade of the immune checkpoint molecule CTLA-4 has not produced significant clinical activity. In PDAC, effector T cells are often scarce within tumor tissue and confined to peritumoral lymph nodes and lymphoid aggregates. We hypothesized that CTLA-4 blockade, despite a lack of clinical efficacy seen thus far in PDAC, might still alter T cell immunobiology, which would have therapeutic implications. Using clinically relevant genetic models of PDAC, we found that regulatory T cells (Tregs), which constitutively express CTLA-4, accumulate early during tumor development but are largely confined to peritumoral lymph nodes during disease progression. Tregs were observed to regulate CD4+, but not CD8+, T cell infiltration into tumors through a CTLA-4/CD80 dependent mechanism. Disrupting CTLA-4 interaction with CD80 was sufficient to induce CD4 T cell infiltration into tumors. These data have important implications for T cell immunotherapy in PDAC and demonstrate a novel role for CTLA-4/CD80 interactions in regulating T cell exclusion. In addition, our findings suggest distinct mechanisms govern CD4+ and CD8+ T cell infiltration in PDAC.

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Section: Resultsmentioning

confidence: 99%

CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer

Bengsch

Knoblock

Liu

et al. 2017

Cancer Immunol Immunother

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“…Recent studies have proposed that FOXP3 is not only expressed by Tregs, but can be expressed by other types of lymphoid or myeloid cells, and by some non-haematopoietic cells such as epithelial cells [40]. To further specify the phenotype of FOXP3+ cells we performed dual immunofluorescence staining on synovial tissue sections with anti-CD4 and anti-FOXP3 antibodies.…”

Section: Resultsmentioning

confidence: 99%

Abatacept reduces synovial regulatory T-cell expression in patients with psoriatic arthritis

Simonyi

Heffernan

Gogarty³

et al. 2017

Arthritis Res Ther

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BackgroundThe aim was to study changes in immunohistochemical expression markers of synovial and skin inflammation, clinical outcomes and magnetic resonance imaging (MRI) scores with abatacept treatment in patients with psoriatic arthritis (PsA).MethodsBiological-treatment-naïve PsA patients with active disease including synovitis of a knee were enrolled in this single-centre, crossover study. Patients were randomised to receive intravenous abatacept 3 mg/kg of body weight or placebo infusion on day 1, 15 and 29; thereafter abatacept 10 mg/kg of body weight was administered every 28 days for 5 months. Clinical data were collected at each visit. Synovial biopsy of the involved knee was obtained at baseline and 2 and 6 months. MRI of the same knee and skin biopsy was performed prior to arthroscopy.ResultsFifteen patients were recruited. Significant improvements in the joint-related measures were observed; 90% were European League Against Rheumatism criteria responders and 30% achieved psoriasis area severity index (PASI)50 at 6 months. Reduction in synovitis (P = 0.016) and vascularity (P = 0.039) macroscopic scores consistent with decrease in total MRI score (P = 0.016) were noticed. Abatacept decreased the immunohistological expression of FOXP3+ cells (P = 0.027), specifically the expression of CD4+FOXP3+ regulatory T cells (Tregs) (P = 0.008) in the synovium over 6 months. There was no significant clinical or immunohistological change in any of the skin measures.ConclusionThis is the first study assessing synovial and psoriatic skin immunpathological changes following abatacept treatment in PsA. Reduction in Treg expression in the synovium but not in the psoriatic lesion suggests abnormal Treg function in PsA with differential suppressive capacity in the synovium compared to the lesional skin. The results of this study demonstrate that abatacept 10 mg/kg of body weight might be an effective treatment option for joint disease in patients with PsA.Trial registrationIrish Health Products Regulatory Authority. Trial registration number: CT 900/489/1 – Abatacept (case number: 2077284, EudraCT Number: 2009-017525-19, Protocol number: 77777). Registered on 12 March 2010.

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“…The ) cells (4). CD patients, however, seem to be more responsive to lactate and show an increase in the total pool of FoxP3 1 cells compared to HC as a possible compensatory mechanism to maintain a high level of functional FoxP3 1 FL isoform (5). During the active state of the disease the small intestine of CD patients is characterized by a drop in lactate levels, an increased intestinal permeability due to the interaction between gliadin and epithelial cells (6) and high production of butyrate from the microbial flora (7).…”

Section: Regulation Of Foxp3 Isoforms In Coeliac Diseasementioning

confidence: 99%

“…T reg cells can mediate suppression of responder cells through different mechanisms, including the production of immunosuppressive cytokines, the consumption of IL-2 and the down-regulation of costimulatory molecules on antigen-presenting cells (APC) [3]. The nuclear transcription factor forkhead box protein 3 (FoxP3) has been described to be fundamental in regulating the differentiation and function of T reg cells [4,5]. Indeed, mutations located on the FOXP3 gene have been associated with the onset of several autoimmune diseases, such as immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), type 1 diabetes, Grave's disease and systemic lupus erythematosus (SLE) [6][7][8][9][10].…”

Section: Regulatory T Cells (T Reg ) Represent a Subset Of Cd4mentioning

confidence: 99%

Proinflammatory cytokine interferon-γ and microbiome-derived metabolites dictate epigenetic switch between forkhead box protein 3 isoforms in coeliac disease

Serena

Shu

Camhi

et al. 2017

Clinical and Experimental Immunology

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SummaryCoeliac disease (CD) is an autoimmune enteropathy triggered by gluten and characterized by a strong T helper type 1 (Th1)/Th17 immune response in the small intestine. Regulatory T cells (T reg ) are CD4 1 CD25 11 forkhead box protein 3 ( FoxP3 1 ) cells that regulate the immune response. Conversely to its counterpart, FoxP3 full length (FL), the alternatively spliced isoform FoxP3 D2, cannot properly down-regulate the Th17-driven immune response. As the active state of CD has been associated with impairments in T reg cell function, we aimed at determining whether imbalances between FoxP3 isoforms may be associated with the disease. Intestinal biopsies from patients with active CD showed increased expression of FOXP3 D2 isoform over FL, while both isoforms were expressed similarly in non-coeliac control subjects (HC). Conversely to what we saw in the intestine, peripheral blood mononuclear cells (PBMC) from HC subjects did not show the same balance between isoforms. We therefore hypothesized that the intestinal microenvironment may play a role in modulating alternative splicing. The proinflammatory intestinal microenvironment of active patients has been reported to be enriched in butyrate-producing bacteria, while high concentrations of lactate have been shown to characterize the preclinical stage of the disease. We show that the combination of interferon (IFN)-g and butyrate triggers the balance between FoxP3 isoforms in HC subjects, while the same does not occur in CD patients. Furthermore, we report that lactate increases both isoforms in CD patients. Collectively, these findings highlight the importance of the ratio between FoxP3 isoforms in CD and, for the first time, associate the alternative splicing process mechanistically with microbial-derived metabolites.

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Foxp3 expression in T regulatory cells and other cell lineages

Cited by 79 publications

References 82 publications

CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer

CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer

Abatacept reduces synovial regulatory T-cell expression in patients with psoriatic arthritis

Proinflammatory cytokine interferon-γ and microbiome-derived metabolites dictate epigenetic switch between forkhead box protein 3 isoforms in coeliac disease

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