Regulatory T cells do not suppress rather activate human basophils by IL-3 and STAT5-dependent mechanisms.

Basophils play an important role in orienting Th2 immune response, and in the pathogenesis of allergic and inflammatory disorders. However, the mechanism by which basophils are kept in check remains unclear and hence we explored the role of regulatory T cells (Treg cells) in this process. We demonstrate that human Treg cells do not suppress rather induce activation of basophils, and promote Th2 responses by IL-3 and STAT5-dependent mechanism.

A Study on the Number of Circulating CD4+CD25+Foxp3+ Regulatory T Cells and CD4+CD25-Foxp3+ T Cells in Psoriasis / 대한피부과학회지

BACKGROUND: Regulatory T cells (Treg) are able to inhibit the immunological response and maintain cutaneous immunological homeostasis, thus preventing autoimmunity against itself. In several studies, the importance of CD4+CD25+Foxp3+ Treg in psoriasis has been examined, using the peripheral blood of patients. However, limited studies on Treg are available and shows conflicting results. Recently, CD4+CD25-Foxp3+ T cells were identified as being the peripheral reservoir of CD4+CD25+Foxp3+ Treg. OBJECTIVE: The purpose of this study was to investigate differences in the CD4+CD25+Foxp3+ Treg and CD4+CD25- Foxp3+ T cell counts between patients with psoriasis and normal controls. METHODS: For phenotypic analysis, the proportions and absolute cell numbers of CD4+CD25+Foxp3+ Treg and CD4+CD25-Foxp3+ T cells in the peripheral blood were examined by flow cytometry. The correlation between the CD4+CD25+Foxp3+ Treg count and other parameters (age of onset, disease duration, BSA, psoriasis area and severity index score, and clinical stage) was also analyzed. RESULTS: Although the CD4+CD25+Foxp3+ Treg count was slightly increased while the number of CD4+CD25- Foxp3+ T cells was slightly decreased in psoriasis patients than that of the controls, the differences between the groups were not statistically significant (5.27+/-2.60 vs. 4.70+/-1.35, p>0.05; 1.56+/-1.07 vs. 1.93+/-1.08, p>0.05). The CD4+CD25+Foxp3+ Treg count did not correlate with the tested parameters except for the clinical stage of psoriasis. The mean+/-SD number of CD4+CD25+Foxp3+ Treg in the stable phase was higher than that in the progressive phase (7.26+/-2.58 vs. 4.35+/-2.10, p0.05). CONCLUSION: These findings suggest that the CD4+CD25+Foxp3+ Treg count alone is insufficient to explain the pathogenesis and severity of psoriasis. However, a decrease in circulating CD4+CD25+Foxp3+ Treg is likely to be correlated with an aggravation of psoriasis.

A Study on the Number of Circulating CD4+CD25+Foxp3+ Regulatory T Cells and CD4+CD25-Foxp3+ T Cells in Psoriasis / 대한피부과학회지

BACKGROUND: Regulatory T cells (Treg) are able to inhibit the immunological response and maintain cutaneous immunological homeostasis, thus preventing autoimmunity against itself. In several studies, the importance of CD4+CD25+Foxp3+ Treg in psoriasis has been examined, using the peripheral blood of patients. However, limited studies on Treg are available and shows conflicting results. Recently, CD4+CD25-Foxp3+ T cells were identified as being the peripheral reservoir of CD4+CD25+Foxp3+ Treg. OBJECTIVE: The purpose of this study was to investigate differences in the CD4+CD25+Foxp3+ Treg and CD4+CD25- Foxp3+ T cell counts between patients with psoriasis and normal controls. METHODS: For phenotypic analysis, the proportions and absolute cell numbers of CD4+CD25+Foxp3+ Treg and CD4+CD25-Foxp3+ T cells in the peripheral blood were examined by flow cytometry. The correlation between the CD4+CD25+Foxp3+ Treg count and other parameters (age of onset, disease duration, BSA, psoriasis area and severity index score, and clinical stage) was also analyzed. RESULTS: Although the CD4+CD25+Foxp3+ Treg count was slightly increased while the number of CD4+CD25- Foxp3+ T cells was slightly decreased in psoriasis patients than that of the controls, the differences between the groups were not statistically significant (5.27+/-2.60 vs. 4.70+/-1.35, p>0.05; 1.56+/-1.07 vs. 1.93+/-1.08, p>0.05). The CD4+CD25+Foxp3+ Treg count did not correlate with the tested parameters except for the clinical stage of psoriasis. The mean+/-SD number of CD4+CD25+Foxp3+ Treg in the stable phase was higher than that in the progressive phase (7.26+/-2.58 vs. 4.35+/-2.10, p0.05). CONCLUSION: These findings suggest that the CD4+CD25+Foxp3+ Treg count alone is insufficient to explain the pathogenesis and severity of psoriasis. However, a decrease in circulating CD4+CD25+Foxp3+ Treg is likely to be correlated with an aggravation of psoriasis.

Effects of fentanyl anesthesia and sufentanil anesthesia on regulatory T cells frequencies.

BACKGROUND: CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) can inhibit anti-tumor immune responses and opioids were also immunosuppressive. We set out to compare the effects of sufentanil and fentanyl on Tregs frequencies both in vitro and in breast cancer (BC) patients undergoing eradicative operation. METHODS: PBMCs from 12 BC patients were activated in vitro in the presence of fentanyl or sufentanil. The percentage of Tregs was detected by flow cytometry after seven days culture. Other 38 patients who underwent eradicative operation were prospectively randomized to sufentanil anesthesia and fentanyl anesthesia. Blood samples were collected for Tregs quantification by flow cytometry analysis and for Foxp3 mRNA expression by RT-PCR, at 10 min before anesthesia (D0), 24h (D1), and 168 h (D7) after the operation respectively. RESULTS: Activation of PBMCs in the presence of either fentanyl or sufentanil increased the Tregs number, and the effect of sufentanil was more significant under the same analgesic effect with fentanyl. In the 38 operated cases, both the Tregs frequencies and Foxp3 mRNA expression on D1 decreased in comparison to those on D0, but then recovered on D7. By comparing SF and F group, there ware no significant differences in Tregs frequencies and Foxp3 mRNA expression on D0, D1 and D7. CONCLUSION: With the same analgesic potency, sufentanil is more powerful in increasing the Tregs quantity than fentanyl in vitro. But there are no significant differences as to Tregs frequencies between sufentanil anesthesia and fentanyl anesthesia perioperatively. Further studies are needed to determine the differences in the Tregs function and long-term outcome of these patients.

Age-related CD4(+)CD25(+)Foxp3(+) regulatory T-cell responses during Plasmodium berghei ANKA infection in mice susceptible or resistant to cerebral malaria.

Different functions have been attributed to CD4(+)CD25(+)Foxp3(+) regulatory T-cells (Tregs) during malaria infection. Herein, we describe the disparity in Treg response and pro- and anti-inflammatory cytokines during infection with Plasmodium berghei ANKA between young (3-week-old) and middle-aged (8-month-old) C57BL/6 mice. Young mice were susceptible to cerebral malaria (CM), while the middle-aged mice were resistant to CM and succumbed to hyperparasitemia and severe anemia. The levels of pro-inflammatory cytokines, such as TNF-α, in young CM-susceptible mice were markedly higher than in middle-aged CM-resistant mice. An increased absolute number of Tregs 3-5 days post-inoculation, co-occurring with elevated IL-10 levels, was observed in middle-aged CM-resistant mice but not in young CM-susceptible mice. Our findings suggest that Treg proliferation might be associated with the suppression of excessive pro-inflammatory Th1 response during early malaria infection, leading to resistance to CM in the middle-aged mice, possibly in an IL-10-dependent manner.

Increased proportion of CD4(+)CD25(+)Foxp3(+) regulatory T cells during early-stage sepsis in ICU patients.

BACKGROUND/PURPOSE(S): We investigated whether CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are induced in patients suffering from early-stage septic shock and distinguish them from noninfectious patients with systemic inflammatory response. METHODS: The study included 37 patients with early-stage septic shock, 15 patients with noninfectious systemic inflammatory response syndrome (SIRS), and 24 heath controls. We prospectively assayed the fraction of Tregs expressing high levels of CD25 and forkhead box P3 (Foxp3) as well as the plasma levels of interferon-γ (IFN-γ), interleukin-4 (IL-4), and soluble CD25 in all the subjects studied. RESULTS: Compared with the control groups, the plasma levels of IFN-γ [66.10 (45.23-85.08) pg/mL vs. 20.97 (17.58-26.21) pg/mL, p < 0.001] and IL-4 [100.69 (77.41-127.68) pg/mL vs. 70.40 (64.14-80.15) pg/mL, p < 0.001] as well as the IFN-γ/IL-4 ratio [0.66 (0.62-0.67) vs. 0.30 (0.27-0.33), p < 0.001] were significantly elevated in the patients with early-stage septic shock, but there was no difference between patients with sepsis and patients with SIRS. We found that the proportion of CD4(+)CD25(+)Foxp3(+) T cells was significantly increased in the patients with early-stage septic shock [(66.82 ± 21.79%) vs. (51.79 ± 21.79%) vs. (56.45 ± 10.68%), p = 0.003] in comparison with the SIRS and control groups, which could be differentiated from the patients with SIRS. The plasma levels of soluble CD25 were also increased, and positively correlated with the proportion of Tregs in patients with early-stage septic shock (Spearman correlation coefficient = 0.390, p = 0.003). CONCLUSION: Our findings indicate that the proportion of CD4(+)CD25(+)Foxp3(+) T cells could be an indicator for the early diagnosis of sepsis. This proportion can also facilitate the evaluation of the patient's immune status and guide suitable immunoregulatory therapy.

Age-Related CD4+CD25+Foxp3+ Regulatory T-Cell Responses During Plasmodium berghei ANKA Infection in Mice Susceptible or Resistant to Cerebral Malaria

Different functions have been attributed to CD4+CD25+Foxp3+ regulatory T-cells (Tregs) during malaria infection. Herein, we describe the disparity in Treg response and pro- and anti-inflammatory cytokines during infection with Plasmodium berghei ANKA between young (3-week-old) and middle-aged (8-month-old) C57BL/6 mice. Young mice were susceptible to cerebral malaria (CM), while the middle-aged mice were resistant to CM and succumbed to hyperparasitemia and severe anemia. The levels of pro-inflammatory cytokines, such as TNF-alpha, in young CM-susceptible mice were markedly higher than in middle-aged CM-resistant mice. An increased absolute number of Tregs 3-5 days post-inoculation, co-occurring with elevated IL-10 levels, was observed in middle-aged CM-resistant mice but not in young CM-susceptible mice. Our findings suggest that Treg proliferation might be associated with the suppression of excessive pro-inflammatory Th1 response during early malaria infection, leading to resistance to CM in the middle-aged mice, possibly in an IL-10-dependent manner.

Immunotherapy of rat glioma without accumulation of CD4(+)CD25(+)FOXP3(+) regulatory T cells.

Immunotherapy may be used for the treatment of glioblastoma multiforme; however, the induced immune response is inadequate when either T cells or dendritic cells are used alone. In this study, we established a novel vaccine procedure in rats, using dendritic cells pulsed with C6 tumor cell lysates in combination with adoptive transfer of T lymphocytes from syngenic donors. On day 21 after tumor inoculation, all the rats were sacrificed, the brains were harvested for calculation of glioma volume, cytolytic T lymphocyte responses were measured by cytotoxic assay, and the frequency of regulatory T lymphocytes (CD4(+)CD25(+)FOXP3(+)) in the peripheral blood was investigated by flow cytometric analysis. The survival rate of rats bearing C6 glioma was observed. Results showed that the co-immunization strategy had significant anti-tumor potential against the pre-established C6 glioma, and induced a strong cytolytic T lymphocyte response in rats. The frequency of peripheral blood CD4(+)CD25(+)FOXP3(+) regulatory T lymphocytes was significantly decreased following the combination therapy, and the rats survived for a longer period. Experimental findings indicate that the combined immunotherapy of glioma cell lysate-pulsed dendritic cell vaccination following adoptive transfer of T cells can effectively inhibit the growth of gliomas in rats, boost anti-tumor immunity and produce a sustained immune response while avoiding the accumulation of CD4(+)CD25(+)FOXP3(+) regulatory T lymphocytes.

Peripheral Generation of CD4+ CD25+ Foxp3+ Regulatory T Cells

CD4+ CD25+ regulatory T cells (Tregs) expressing the lineage-specific marker Foxp3 represent an important regulatory T cell that is essential for maintaining peripheral tolerance. Although it was believed that Treg development is solely dependent on the thymus, accumulating evidence demonstrates that Tregs can also be induced in the periphery. Considering the various origins of peripherally developed CD4+ CD25+ Foxp3+ regulatory T cells, it seems likely that multiple factors are involved in the peripheral generation of Tregs.