Identification of the Microrna Signature of Acute Myeloid Leukemia Patient s Regulatory T Lymphocytes
Rédouane RouasMakram MerimiBassam BadramArsène BurnyDominique BronPhilippe LewalleHussein Fayyad Kazan
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To study the proportion of regulatory T cells (Tregs) in peripheral blood of patients with rheumatoid arthritis (RA) and investigate the significance of Tregs change in the incidence and inflammatory activity of RA.Three-color fluorescence flow cytometry was used to detect the CD4, CD25 and CD127 markers in the peripheral blood lymphocytes of 25 RA patients and 31 healthy volunteers (HVs). The proportions of CD4(+)CD25(+), CD4(+)CD25(high), CD4(+)CD25(+)CD127(-) and CD4(+)CD25(high)CD127(-) cells were compared between the two groups and correlation analysis was conducted between Tregs and disease activity indices which including disease activity score (DAS28-4), tender joint count (TJC), swollen joint count (SJC), time of morning stiffness, patient's global assessment of disease activity on a 100 mm VAS by doctor and patients, erythrocyte sedimentation rate and C-reactive protein.The proportions of CD4(+)CD25(+)CD127(-) and CD4(+)CD25(high)CD127(-) cells in CD4(+) peripheral T lymphocytes were (2.53 +/- 0.85)% and (0.91 +/- 0.32)% respectively in RA group, while they were (3.22 +/- 0.97)% and (1.25 +/- 0.41)% in HV group. Both of the proportions of CD4(+)CD25(+)CD127(-) and CD4(+)CD25(high)CD127(-) cells were lower in RA group comparing with HV group, and both were significantly different between the two groups (P < 0.05). Correlation analysis indicated significant negative correlations of the proportions of CD4(+)CD25(+)CD127(-) and CD4(+)CD25(high)CD127(-) cells with DAS28-4 and TJC (P < 0.05), furthermore, CD4(+)CD25(high)CD127(-) T cells still showed significant negative correlation with the SJC and patient's global assessment of disease activity on a 100 mm VAS by patients (P < 0.05).The proportion of Tregs decreased in peripheral blood lymphocytes of patients with RA and the abnormality of Tregs may play an important role in the incidence and inflammatory activity of RA.
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To investigate numbers and function of CD25(+) regulatory T cells (Tregs) that lack IL-7 receptor (CD127) expression in RA.Numbers of CD4 T cells expressing either CD25 or CD127, and those co-expressing or lacking both CD25 and CD127 were assessed in peripheral blood (PB) of RA patients and healthy controls, and in paired samples of SF and PB from RA patients. All T-cell subsets were analysed for FoxP3 expression. The anergic state and the capacity to suppress CD127(+) proliferating responder T cells were determined.Numbers of CD127(-) T cells and CD25(+) Tregs in PB of RA patients were not different from controls but significantly increased in SF compared with PB. CD25(+) and CD127(-) T cells showed comparable FoxP3 expression. CD127(+) T cells hardly expressed FoxP3. PB CD25(+)CD127(-) T cells identified a subset that consisted for 75% of FoxP3(+) cells. SF CD25(+)CD127(-) T-cell number was increased; however, in SF fewer of these cells were FoxP3(+). CD25(+)CD127(-) T cells were anergic, and in controls potent suppressors of CD127(+) proliferating T cells, but in RA patients these cells showed impaired suppression. In line with this, IL-7 had an increased capacity to activate total CD4 T cells from SF as compared with PB despite increased numbers of CD25(+)CD127(-) in SF.These data demonstrate improved identification of FoxP3(+) T cells in RA patients by the absence of CD127 in addition to CD25 expression. Increased numbers of CD25(+)CD127(-) T cells are found in inflamed RA joints, but they have an impaired suppressive function, which could contribute to the persistent arthritis in these patients.
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Abnormalities in CD4+CD25+Foxp3+ regulatory T (T reg) cells have been implicated in susceptibility to allergic, autoimmune, and immunoinflammatory conditions. However, phenotypic and functional assessment of human T reg cells has been hampered by difficulty in distinguishing between CD25-expressing activated and regulatory T cells. Here, we show that expression of CD127, the α chain of the interleukin-7 receptor, allows an unambiguous flow cytometry–based distinction to be made between CD127lo T reg cells and CD127hi conventional T cells within the CD25+CD45RO+RA− effector/memory and CD45RA+RO− naive compartments in peripheral blood and lymph node. In healthy volunteers, peripheral blood CD25+CD127lo cells comprised 6.35 ± 0.26% of CD4+ T cells, of which 2.05 ± 0.14% expressed the naive subset marker CD45RA. Expression of FoxP3 protein and the CD127lo phenotype were highly correlated within the CD4+CD25+ population. Moreover, both effector/memory and naive CD25+CD127lo cells manifested suppressive activity in vitro, whereas CD25+CD127hi cells did not. Cell surface expression of CD127 therefore allows accurate estimation of T reg cell numbers and isolation of pure populations for in vitro studies and should contribute to our understanding of regulatory abnormalities in immunopathic diseases.
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Abstract A major obstacle hampering the therapeutic application of regulatory T (Treg) cells is the lack of suitable extracellular markers, which complicates their identification/isolation. Treg cells are normally isolated via CD25 (IL‐2Rα) targeting, but this protein is also expressed by activated CD4 + effector T (Teff) lymphocytes. Other extracellular (positive or negative) Treg selection markers (e.g., HLA‐DR, CD127) are also nonspecific. CD26 is an extracellular peptidase whose high expression has been traditionally used as an indicator of immune activation and effector functions in T cells. Now, we provide flow cytometry data showing high levels of CD26 within CD4 + CD25 − or CD4 + FoxP3 −/low effector T (Teff) lymphocytes, but negative or low levels (CD26 −/low ) in Treg cells selected according to the CD4 + CD25 high or the CD4 + FoxP3 high phenotype. Unlike the negative marker CD127 (IL‐7Rα), which is down modulated in CD4 + Teff lymphocytes after TCR triggering, most of these cells upregulate CD26 and take a CD4 + CD25 +/high CD26 + phenotype upon activation. In contrast, there is only a slight upregulation within Treg cells (CD4 + CD25 high CD26 −/low ). Thus, differences in CD26 levels between Treg and Teff subsets are stable, and assessment of this marker, in combination with others like CD25, FoxP3, or CD127, may be useful during the quantitative evaluation or the isolation of Treg cells in samples containing activated Teff lymphocytes (e.g., from patients with autoimmune/inflammatory diseases). © 2012 International Society for Advancement of Cytometry
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It has recently been suggested that a lack of CD127 expression can be used to identify human CD4 þ regulatory T cells (Tregs), especially when combined with CD25. Therefore, we analyzed CD4 þ CD25 þ CD127 low/� cells and compared their frequency and expression pattern with those of FoxP3 þ Tregs using multiparameter flow cytometry analysis. We obtained human peripheral blood cells from 20 normal healthy donors and determined the number of CD25 þ CD127 low/� cells as a percentage of CD4 þ T cells in the same panel used for CD4 þ CD25 þ FoxP3 þ cells. In contrast to CD4 þ CD25 þ FoxP3 þ cells, gating of a clear CD4 þ CD25 þ CD127 low/� population was difficult. Moreover, we demonstrated that there was a high percentage (34.0±15.1%) of CD127 low/� cells that did not express FoxP3 and, conversely, that there was a high percentage (30.3±7.4%) of CD127 þ cells that expressed FoxP3, suggesting that these markers did not represent the same population of Tregs. These data were also confirmed in blood samples from patients with systemic scleroderma. Thus, isolation of pure Treg populations for in vitro functional studies is a challenge, explaining the varying results by different groups in clinical studies. The data from this study have important implications for carrying out a quantitative analysis of Tregs in human samples.
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To investigate the level of CD4+ CD25+ Foxp3+ regulatory T cells and observe relation between expression of Foxp3 and CD127 in peripheral blood of chronic HBV infection.CD4+ CD25+ Foxp3+ and CD4+ CD25+ CD127low Treg in peripheral blood from 34 patients of immune tolerance stage, 26 patients of immune clearance stage and 31 patients of non-active status were quantitatively analyzed by flow cytometry.Immune tolerance group presented a higher fraction of CD4+ CD25+ Foxp3+ and CD4+ CD25+ CD127low Treg than non-active group in chronic HBV infection (Z = -2.693, P = 0.007 and t = 3.251, P = 0.002), and HBV positive group also presented a higher fraction than non-active group (t = 2.266, P = 0.026 and t = 3.208, P = 0.002), But ALT normal group is similar to ALT abnormal group (P > 0.05). In this study, the relation between expression of CD127low and Foxp3+ from CD4+ CD25+ regulatory T cells was observed, and CD4+ CD25+ CD127low Treg presented a higher fraction than CD4+ CD25+ Foxp3+ Treg.Peripheral Treg in HBV active replication group is higher than HBV negative group of chronic HBV infection. Expression of CD127low is consistent with Foxp3+ in CD4+ CD25+ regulatory T cells, but the former is significantly higher than the latter.
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The quantitative identification and enrichment of viable regulatory T cells (Treg) requires reliable surface markers that are selectively expressed on Treg. Foxp3 is the accepted marker of natural Treg, but it cannot be used to isolate cells for functional studies. CD127 is a new surface marker expressed in Treg cells. In this study, two populations of Treg, including CD4(+)CD25(+)CD127(low/-) and CD4(+)CD25(+)Foxp3(+)T cells, and profiles of the Foxp3 expression in CD4(+)CD25(+)CD127(low/-) cells were compared to evaluate which population is better. The peripheral blood cells were collected and spleen suspension of BALB/C mice were prepared, and using triple staining CD4, CD25, CD127 and CD4, CD25, Foxp3. The profiles of Treg, including CD4(+)CD25(+)CD127(low/-) and CD4(+)CD25(+)Foxp3(+) were detected by flow cytometry. The quadruple staining CD4, CD25, Foxp3 and CD127 were used to determine the CD127 expression in CD4(+)CD25(+)Foxp3(+) cells. The results showed that on T cell subset the median expression levels of CD4(+), CD4(+)CD25(+) were 39.02%, 5.35% in peripheral blood and 23.49%, 3.86% in spleen. On CD4(+) T cell subset, the median expression level of CD4(+)CD25(+)CD127(low/-) and CD4(+)CD25(+)Foxp3(+)T cells were 7.13%, 3.97% in peripheral blood and 12.8%, 8.23% in spleen. The ratio of CD4(+)CD25(+)CD127(low/-) T cells was higher than that of CD4(+)CD25(+)Foxp3(+) cells in both peripheral blood and spleen cells (P < 0.01). The CD4(+)CD25(+)CD127(low/-) cells highly expressed Foxp3, while the CD4(+)CD25(+)Foxp3(+)T cells lowly expressed CD127. It is concluded that compared with the CD4(+)CD25(+)Foxp3(+) populations, CD4(+)CD25(+)CD127(low/-) T cells better fit the definition of naturally occurring regulatory T cells in peripheral blood cells and spleen of BALB/C mice. CD127(low/-) is a characteristic marker on surface of CD4(+)CD25(+) Treg cells, and has been confirmed to be more specific marker for quantitatively sorting Treg cells.
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