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Background: Recently, identification of CD25 (interleukin-2 receptor alpha) expression on leukemic blasts was correlated to early treatment failure and unfavorable outcome in acute myeloid leukemia (AML) patients. Here we wished to determine whether quantification of CD25 on peripheral blood CD4+ T cells could improve prognostication in newly diagnosed AML patients., Methods: The mean fluorescence intensity (MFI) of CD25 expression and frequencies of peripheral blood CD4+ T cells with varying levels of CD25 and CD127 expression were assessed by flow cytometry in all studied individuals., Results: Using univariate (unadjusted) and multivariate (adjusted) analyses we demonstrated that detection of high pretreatment CD25 expression on circulating CD4+ T cells was associated with significantly decreased survival rate of AML patients subjected to standard induction chemotherapy. These associations held true for both entire group of analyzed AML patients and different subgroups of patients identified by presence or absence of favorable and adverse molecular prognostic factors., Conclusions: Our data indicate that quantification of CD25 expression on peripheral blood CD4+ T cells could become a novel, easily accessible method of shortened survival prognostication of AML patients subjected to standard cytotoxic therapy., (Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Introduction: Recent studies in a mouse model of chronic lymphocytic leukemia (CLL) demonstrated that inhibition of the programmed death receptor 1 (PD‑1)-PD‑L1 axis resulted in correction of leukemia‑induced CD8+ T cell‑related immune dysfunction and protected mice against CLL development. However, it remains unclear whether CLL development and progression can be also associated with CD4+ T cells expressing PD‑1., Objectives: We aimed to analyze whether a quantitative assessment of CD4+PD‑1+ T cells performed at the time of diagnosis can have prognostic significance in patients with CLL., Patients and Methods: We examined 56 patients with newly diagnosed CLL at different stages of the disease. The quantitative assessment of PD‑1‑expressing CD4+ T cells was performed in all patients, using multicolor flow cytometry., Results: We demonstrated that CLL patients with an advanced (high and intermediate risk) stage had a significantly higher number of CD4+PD‑1+ T cells compared with subjects with low‑grade disease. Importantly, we showed that the number of PD‑1‑expressing CD4+ T cells in the peripheral blood of patients referred for immediate treatment due to the advanced stage of the disease was significantly higher compared with subjects on watchful waiting. Finally, we found that treatment‑naive patients with higher numbers of CD4+PD‑1+ T cells at baseline showed a significantly shortened time to the first treatment compared with patients with a low number of CD4+PD‑1+ T cells., Conclusions: Our study showed that the quantative assessment of CD4+PD‑1+ T cells in peripheral blood using flow cytometry can facilitate prognostication of patients with newly diagnosed CLL.

The role of adaptive immune system in regulation of asthmatic responses remains elusive. Here, we performed a comprehensive time-course analysis of mutual relationships between development of asthmatic response following allergen challenge and changes in several CD4+ T cell subsets which we characterized as either releasing interleukin-10 (CD4+CD25-CD127- and CD4+CD25+CD127+ T cells) or responding to IL-10 (CD4+ T cell subsets expressing CD210). Patients that developed asthmatic reaction were described as responders (R) whereas the others were named non-responders (NR). In R, in contrast to NR, at 6 h, we demonstrated significant expansion of CD4+CD25-CD127- T cells which was followed by drop to baseline values at 24 h. In contrast, in R, we observed decrease in numbers of CD4+CD25+CD127+ and CD4+CD25-CD127+ T cells at 24 h. Interestingly, at baseline, despite comparable IL-10 levels, R presented with lower levels of all CD4+ T cell subsets expressing CD210. In R, the numbers of CD4+CD210+ T cell subsets were further decreased following bronchial challenge which was paralleled by decrease in IL-10 serum levels. Altogether, our data suggest that dynamic interactions between IL-10-producing and IL-10-responding CD4+ T cells could contribute to pathogenesis of asthmatic responses in atopic individuals.

Pathobiology of type 1 diabetes (T1D) is predominantly associated with T-cell-related actions. Homeostasis of majority of T-cells is critically dependent on signals mediated by CD127 (interleukin-7 receptor, IL-7R). In contrast, regulatory T-cells express very little CD127 and thereby may be delineated by CD4+CD25+CD127- phenotype. Here we aimed to analyze CD127 expression on CD4+ and CD8+ T-cells and enumerate CD4+CD25+CD127- T-cells in long-lasting T1D. T-cells were analyzed by flow cytometry and immunologic data were correlated with vascular, metabolic, and inflammatory parameters. We demonstrated significantly decreased CD127 levels on CD4+, but not CD8+, T cells in T1D pediatric patients. Interestingly, frequencies of CD4+CD25+CD127- T-cells were significantly enhanced in T1D children and correlated well with frequencies of CD34+CD144+ endothelial progenitor cells and CD4+CD25- T-cells. Levels of CD127 on both CD4+ and CD8+ T-cells in T1D patients were not correlated to each other or HbA1C. Interestingly, however, CD127 levels on CD4+ T-cells were significantly correlated to frequencies of CD4+CD25+CD127- T-cells, whereas CD127 levels on CD8+ T-cells were significantly correlated to concentrations of VEGF and triglycerides. Our data indicate that CD127 expression is differentially modulated on CD4+ and CD8+ T-cells in the course of T1D. Moreover, we demonstrated that, in contrast to recent-onset T1D, long-lasting T1D is associated with enhancement of T-cells with regulatory phenotype.

Despite widely acknowledged contributions of innate and adaptive immune systems to the pathogenesis of allergic diseases, mutual interactions occurring in vivo between components of those two systems have not been studied in sufficient detail. Here, we wished to investigate whether phenotypic features of monocytes and CD4+ T cells in allergic patients are reciprocally related. Therefore, we recruited 50 untreated house dust mite-sensitive allergic rhinitis patients and 29 non-atopic healthy individuals and performed comprehensive simultaneous flow cytometric analysis of mutual correlations between levels of CD14, CD16, CD163, CD206, CD124 (IL-4R), CD210 (IL-10R) and CD25, CD124, CD127 (IL-7R), CD210, ICOS expression on monocytes and CD4+ T cells, respectively. We found that CD163 monocyte expression in allergic but not healthy subjects is positively correlated with monocyte IL-10R, and, to a lesser extent, CD206, but not IL-4R expression. Levels of CD163 expression were not related to frequencies of CD14++CD16-, CD14++CD16+, and CD14+CD16++ monocyte subsets. In contrast to healthy controls, intensities of monocyte IL-10R in allergic individuals were significantly correlated with monocyte CD206 and IL-4R expression. In addition, levels of monocyte IL-4R and IL-10R monocyte expression were positively correlated to expression of IL-4R and IL-10R on CD4+ T cells in both groups of studied subjects. Interestingly, we demonstrated a significant positive correlation between levels of monocyte CD206 expression and levels of IL-10R and IL-4R expression on CD4+ T cells in allergic but not healthy individuals. In summary, we conclude that allergic rhinitis is associated with a number of phenotypic alterations of circulating monocytes and CD4+ T cells., (Copyright © 2013 S. Karger AG, Basel.)

Our purpose was to evaluate the effects of short-term oral glucocorticoid (GC) treatment on frequencies of T cells with putative regulatory phenotype (namely, CD4+CD25+CD127- and CD4+CD25high) in patients with asthma exacerbations. In addition, we sought to determine frequencies of above T cell subsets in adult asthmatic patients in relation to disease severity and different treatment regimens. The analysis was performed in 62 patients with different stages of asthma and ten healthy controls. Polychromatic flow cytometry was applied to delineate T cells with CD4+CD25+CD127- and CD4+CD25high phenotype. Exhaled nitric oxide analysis was used to assess allergic airway inflammation. Levels of neither CD4+CD25+CD127- nor CD4+CD25high T cells were significantly altered after 7-day oral GC treatment. Importantly, there were no detectable differences in frequencies of those cells among studied groups of asthmatics with different severity of disease and healthy controls. Moreover, levels of CD4+CD25+CD127- and CD4+CD25high T cells in asthmatic patients were not correlated to exhaled nitric oxide concentrations. Our data indicate that neither effects of average doses of oral GC treatment nor disease severity are related to changes in frequencies of CD4+CD25+CD127- and CD4+CD25high T cells in adult asthmatic patients.

Background: Recent studies in rodents revealed that regulatory T cells (T reg cells) with CD4+CD25+ phenotype can exert suppressive effects on experimentally-induced allergic airway inflammation and airway hyper-reactivity. It is unclear however, whether modulations of bronchoconstriction responses in human subjects might be related to T reg cells. We report here for the first time the changes in frequency of circulating lymphocytes with putative T reg cell phenotype (CD4+CD25+CD127low) in relation to bronchoconstriction phenotype following an intrabronchial allergen challenge., Material and Methods: Thirty-one house dust mite sensitive patients were challenged with Dermatophagoides pteronyssinus extract (Dp). Eleven isolated early responders (IER) were compared with nine dual (early and late) responders (DR) and to 11 non-responders (NR). Frequencies of peripheral blood CD4+CD25+CD127low lymphocytes were assessed in all groups of patients by using three-parameter flow cytometry before, and six and 24 h, after allergen inhalation., Results: At baseline, frequencies of CD4+CD25+CD127low lymphocytes were not statistically different among NR, IER and DR. When all individuals were analyzed together, a statistically significant decrease in frequency of CD4+CD25+CD127low lymphocytes was observed 6 h after the bronchial challenge. Interestingly, such a pattern was found consistently only in NR, while IER and DR displayed varying responses resulting in a trend similar to that of NR. Twenty-four hours after the bronchial challenge, frequencies of CD4+CD25+CD127low lymphocytes in all groups tended to return to baseline values., Conclusions: Our data indicate that bronchial allergen inhalation in sensitive patients (predominantly in those who did not develop significant bronchoconstriction) is associated with a decrease of proportion of peripheral lymphocytes with regulatory T cell phenotype.

IL-2, the first cytokine discovered with T cell growth factor activity, is now known to have pleiotropic effects on T cells. For example, it can promote growth, survival, and differentiation of Ag-selected cells, or facilitate Ag-induced cell death of T cells when Ag persists, and in vivo, it is thought to contribute to the regulation of the size of adaptive T cell response. IL-2 is deficient in HIV-1 infection and has been used in the management of HIV-1-infected individuals undergoing antiretroviral therapy. In this study, we investigated how continuous low-dose IL-2 affected the CD4+ and CD8+ T cell response induced by two inoculations of a canarypox recombinant SIV-based vaccine candidate in healthy macaques chronically infected with SIVmac251. These macaques had normal levels of CD4+ T cells at the beginning of antiretroviral therapy treatment. Vaccination in the presence of IL-2 significantly augmented Gag-specific CD8+ T cell responses, but actually reduced Gag-specific CD4+ T cell responses. Although IL-2 at low doses did not change the overall concentration of circulating CD4+ or CD8+ T cells, it expanded the frequency of CD4+CD25+ T cells. Depletion of the CD4+CD25+ T cells in vitro, however, did not result in a reconstitution of Gag-specific CD4+ responses or augmentation of SIV-specific CD8+ T cell responses. Thus, we conclude that the decrease in virus-specific CD4+ T cell response may be due to IL-2-promoted redistribution of cells from the circulation, or due to Ag-induced cell death, rather than suppression by a T regulatory population.

Interleukin-7 (IL-7) regulates T-cell homeostasis, and its availability is augmented in lymphopenic hosts. Naive CD8+ T cells transferred to lymphopenic mice acquire a memory-like phenotype, raising the possibility that IL-7 is the biological mediator of this effect. Here, we provide direct evidence that IL-7 induces the acquisition of memory-cell markers not only in CD8+ T cells but also in CD4+ T-cell subsets in immune-competent Indian rhesus macaques. The increase of these memory-like populations was dependent on the dose of the cytokine, and these cells were found in the blood as well as secondary lymphoid organs. Memory-like CD4+ and CD8+ T cells acquired the ability to secrete tumor necrosis factor alpha and, to a lesser extent, gamma interferon following stimulation with a cognate antigen. The phenotypic change observed in naive T cells was promptly reversed after discontinuation of IL-7. Importantly, IL-7 induced cycling of both CD4+ and CD8+ central memory and effector memory T cells, demonstrating its contribution to the maintenance of the entire T-cell pool. Thus, IL-7 may be of benefit in the treatment of iatrogenic or virus-induced T-cell depletion., (Copyright 2004 American Society for Microbiology)