Immune response failure against hepatitis C virus (HCV) has been associated with an increased regulatory T cell (Treg) activity. After liver transplantation (LT), 80% of patients experience an ...accelerated progression of hepatitis C recurrence. The aim of this work was to assess the involvement of Tregs, T helper (Th) 1, 2 and 17 cells in recurrent hepatitis C.
Peripheral blood cells obtained before and one month after LT from 22 recipients were analysed. Forty-four key molecules related to Treg, Th1, 2 and 17 responses, were evaluated using qRT-PCR. Liver recipients were classified in two groups according to graft fibrosis evaluated by the METAVIR score on the biopsy performed one year after LT (mild: F ≤ 1, n = 13; severe: F > 1, n = 9). Patients developing a severe recurrence were compared with patients with a mild recurrence.
mRNA levels of Treg markers obtained one month after LT were significantly increased in patients with a severe disease course when compared to patients with a mild recurrence. Markers of the Th1 response were elevated in the same group. No differences in the markers determined before LT were observed.
These findings suggest that Treg, induced by a multifactorial process, which could include a strong Th1 response itself, may play a role in suppressing the early antiviral response, leading to a severe recurrence of hepatitis C.
Upon activation by its ligand hepatocyte growth factor/scatter factor, the receptor tyrosine kinase Met promotes survival, proliferation, and migration of epithelial cells during embryogenesis. ...Deregulated Met signaling can also promote cancer progression and metastasis. Met belongs to the functional family of dependence receptors whose activity switches from pro-survival to pro-apoptotic during apoptosis upon caspase cleavage. Although apoptosis resistance is a hallmark of cancer cells, some remain sensitive to other cell death processes, including necrosis induced by calcium stress. The role and fate of Met during necrotic cell death are unknown. Following treatment with calcium ionophores, cell lines and primary cells undergo necrosis, and the full-length Met receptor is efficiently degraded. This degradation is achieved by double cleavage of Met in its extracellular domain by a metalloprotease of the A disintegrin and metalloproteinase (ADAM) family and in its intracellular domain by calpains (calcium-dependent proteases). These cleavages separate the Met extracellular region from its kinase domain, thus preventing Met activity and its potential pro-survival activity. Although the intracellular fragment is very similar to the fragment generated by caspases, it displays no pro-apoptotic property, likely because of the presence of the last few amino acids of Met, known to inhibit this pro-apoptotic function. The fragments identified here are observed in lung tumors overexpressing the Met receptor, along with fragments previously identified, suggesting that proteolytic cleavages of Met are involved in its degradation in tumor tissues. Thus, Met is a modulator of necrosis, able to protect cells when activated by its ligand but efficiently degraded by proteolysis when this process is engaged.
Immune response failure during HCV infection has been associated with the activity of regulatory T cells. Hepatitis C‐related cirrhosis is the main reason for liver transplantation. However, 80% of ...transplanted patients present an accelerated recurrence of the disease. This study assessed the involvement of regulatory T‐cell subsets (CD4+CD25+ cells: ‘Treg’ and CD49b+CD18+ cells: ‘T regulatory‐1’ cells), in the recurrence of HCV after liver transplantation, using transcriptomic analysis, ELISA assays on serum samples and immunohistochemistry on liver biopsies from liver recipients 1 and 5 years after transplantation. Three groups of patients were included: stable HCV‐negative recipients and those with mild and severe hepatitis C recurrence. At 5 years, Treg markers were overexpressed in all HCV+ recipients. By contrast, Tr1 markers were only overexpressed in patients with severe recurrence. At 1 year, a trend toward the overexpression of Tr1 was noted in patients evolving toward severe recurrence. IL‐10 production, a characteristic of the Tr1 subset, was enhanced in severe recurrence at both 1 and 5 years. These results suggest that Tr1 are enhanced during severe HCV recurrence after liver transplantation and could be predictive of HCV recurrence. High levels of IL‐10 at 1 year could be predictive of severe recurrence, and high IL‐10 producers might warrant more intensive management.
This study of regulatory T cell subsets (CD4+CD25+ cells: “Treg” and CD49b+CD18+ cells: “T regulatory‐1” cells) in recurrence of HCV after liver transplantation found that Tr1 are enhanced during severe HCV recurrence.
Introduction Exosomes are nanovesicles found in large quantities in biological fluids and tumors of patients with nasopharyngeal carcinoma (NPC). These tumor exosomes play an important role in tumor ...progression due to their immunosuppressive properties. In addition, it has been reported that the frequency and suppressor functions of CD4 + CD25highFOXP3 + CD127low regulatory T cells (Treg) are also higher in NPC patients than healthy donors. Interactions between NPC-derived exosomes and Treg remain unknown. Here we investigated their ability to induce, expand, activate and recruit human Treg. Material and methods Treg recruitment by exosomes derived from NPC cell lines (C15/C17-Exo), exosomes isolated from NPC patients’ plasma (Patient-Exo), and CCL20 was tested in vitro using Boyden chamber assays and in vivo using a xenograft SCID mouse model ( N = 5), both in the presence and absence of anti-CCL20 monoclonal antibodies (mAb). Impact of these NPC exosomes (NPC-Exo) on Treg phenotype and function was determined using adapted assays (FACS, Q-PCR, ELISA and MLR). Experiments were performed in comparison with exosomes derived from plasma of healthy donors (HD-Exo). Results CCL20 allowed the intra-tumoral recruitment of human Treg. NPC-Exo also facilitated Treg recruitment (3.30 ± 0.34-fold increase, P < .001), which was statistically significantly inhibited ( P < .001) by an anti-CCL20 blocking mAb. NPC-Exo also recruited conventional CD4 + CD25- T cells and mediated their conversion into inhibitory CD4 + CD25high cells. Moreover, NPC-Exo statistically significantly enhanced ( P = 0.0048) the expansion of human Treg, inducing the generation of Tim3Low Treg with increased expression of CD25 and FOXP3. Finally, NPC-Exo induced an overexpression of cell markers associated with Treg phenotype, properties and recruitment capacity. For example, GZMB mean fold change was 21.45 ± 1.75. These results were consistent with a stronger suppression of responder cells’ proliferation ( P < .001), and the secretion of immunosuppressive cytokines (IL10, TGFB1). Conclusion Interactions between NPC-Exo and Treg represent a newly defined mechanism that may be involved in regulating peripheral tolerance by tumors and in supporting immune evasion in human NPC.
Abstract Background Inevitable hepatitis C virus (HCV) recurrence after liver transplantation is a major barrier to the survival of a transplanted liver. It may be promoted by immunosuppression and ...the emergence of CD4+ CD25+ regulatory T cells (Treg). Treg cells can mediate the induction and maintenance of immunological self-tolerance as well as transplant tolerance. We investigated the effects of cyclosporine (CsA), a widely used immunosuppressive agent, on human CD4+ CD25+ Treg cells. Methods Human CD4+ CD25+ cells isolated from healthy donors were cultured in the presence of 40 or 400 ng/mL CsA. The suppressive activity of Treg was assessed in mixed leukocyte reactions (MLR) using CD25+ and autologous activated peripheral blood mononuclear cells (PBMC). Phenotype analysis (flow cytometric, Q-PCR) and cytokine production (ELISA) of Treg cells were then performed on cultures. Results CsA (40 or 400 ng/mL) inhibited the proliferative capacity of PBMC and CD4+ CD25+ Treg in a dose-dependent manner. Interestingly, addition of 40 ng/mL CsA in MLR impaired the suppressive activity of CD4+ CD25+ cells, whereas a higher dose of CsA had no effect on Treg function. It appears that a therapeutic dose of CsA (40 ng/mL) did not change the phenotype of CD4+ CD25+ T cells, but altered Treg activity by switching the regulatory to an inflammatory cytokine profile. Conclusion CsA significantly impaired the function of CD4+ CD25+ Treg cells by inducing interleukin-2 (IL-2) and interferon-γ (IFN-γ) secretion. The present studies suggested that CsA may block the induction of immune tolerance and decrease the risk of hepatitis C recurrence.
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