Lourdes Arruvito

Expansion of CD4+CD25+and FOXP3+ Regulatory T Cells during the Follicular Phase of the Menstrual Cycle: Implications for Human Reproduction

Regulatory T cells (Tregs) are thought to affect the severity of various infectious and autoimmune diseases. The incidence of autoimmune disease is higher in fertile women than in men. Thus, we investigated whether Treg numbers were modulated during the menstrual cycle by sex hormones. In fertile nonpregnant women, we detected an expansion of CD4+CD25+FOXP3+ Tregs in the late follicular phase of the menstrual cycle. This increase was tightly correlated with serum levels of estradiol and was followed by a dramatic decrease in Treg numbers at the luteal phase. Women who have had recurrent spontaneous abortions (RSA) showed similarly low numbers of Tregs at both the follicular and luteal phases, comparable to numbers we observed in postmenopausal women. In addition to decreased numbers, Tregs from women with RSA were also functionally deficient, as higher numbers were required to exert a similar magnitude of suppression to CD4+CD25+FOXP3+ cells from fertile women. Consequently, reproductive failure might result from the inability of Tregs in women with RSA to expand during the preimplantatory phase combined with their lower functional capacity. Additionally, the modulation of Treg numbers we observed in fertile women suggests that the stage of the menstrual cycle should be taken into account when Treg numbers are investigated clinically.

NK Cells Expressing a Progesterone Receptor Are Susceptible to Progesterone-Induced Apoptosis

It has been proposed that progesterone (P4) induces the suppression of immune responses, particularly during pregnancy. However, knowledge about the mechanisms involved has remained largely elusive. We demonstrate herein that peripheral blood NK (PBNK) cells express both classical progesterone receptor (PR) isoforms and are specifically affected by the actions of P4 through two apparently independent mechanisms. Progesterone induces caspase-dependent PBNK cell death, which is reversed by two different anti-progestins, ZK 98.299 and RU 486, supporting the involvement of classical PR isoforms. It was suggested that CD56brightCD16− killer Ig-like receptor (KIR)− NK cells might represent precursor cells, which, upon activation, acquire the features of a more mature NK subset expressing KIR receptors. The present study demonstrates that PR expression seems to be restricted to more mature KIR+ PBNK cells. The expression of PR had a functional counterpart in the suppressive effect of P4 on IL-12-induced IFN-γ secretion. This cytokine suppression was mainly observed in KIR+ PBNK cells, without affecting the high secretion of IFN-γ by CD56bright PBNK cells. The lack of PR expression on CD56brightKIR− PBNK cells provides an additional phenotypic marker to test the idea that they might represent the PBNK precursors selectively recruited into the endometrium where they differentiate to become the uterine NK cells. Additionally, these findings may be relevant to NK cell function in viral immunity, human reproduction, and tumor immunity.

IL-6 trans-signaling and the frequency of CD4+FOXP3+ cells in women with reproductive failure

Pregnancy constitutes a major challenge to the maternal immune system, as it requires tolerance of paternal alloantigen. Maternal rejection of the fetus may develop when T regulatory (Treg) cells fail to control the balance between tolerance and immunity. Increasing evidence supports the role of IL-6 trans-signaling within T cells as a key pathway for blockade of the development of adaptive Treg cells. The present study investigated whether alteration of the components of the IL-6 trans-signaling might be a mechanism associated with modified immune responses in patients experiencing recurrent spontaneous abortion (RSA). In contrast with control women, sera from RSA women induced an enhanced mixed lymphocyte reaction (MLR) against paternal PBMCs, showing increased proliferation and lack of MLR-blocking factor activity. The sera from RSA women inhibited expansion of the FOXP3+ T cell population in TCR-activated PBMCs and showed an imbalance in levels of soluble components of the IL-6 trans-signaling pathway. In comparison with fertile women, those with RSA showed significantly increased levels of soluble IL-6 receptor and IL-6, and decreased levels of soluble gp130, the trans-signaling inhibitor. Finally we found that paternal alloimmunization acts to modulate serum levels of factors involved in the IL-6 trans-signaling pathway and increases the frequency of Treg cells. Consequently, women with reproductive failure show evidence of alteration in the IL-6 trans-signaling pathway which might be associated with abnormal performance of Treg cells in mediating feto-maternal tolerance.

A physiological role for inducible FOXP3+ TREG cells: Lessons from women with reproductive failure

We have previously shown a decreased frequency and function of Tregs in women suffering from recurrent spontaneous abortions (RSA). In the current study, we first investigated the expression of FOXP3 after T-cell activation. We observed that expression of FOXP3 in activated PBMCs was already present above baseline before any cell division, indicating that it was induced in cells that were previously negative for this transcription factor. Because RSA women showed a more limited expansion of FOXP3-positive cells, we next assessed the role of IL-2 signaling through STAT5, which is known to be required for generation of inducible Tregs (iTregs). We demonstrated not only that TGF-beta and IL-2 were diminished but also that the IL-2-STAT-5 signaling axis was down regulated in RSA women. Finally, in addition to a limited FOXP3(+) cells expansion in vitro, iTregs from RSA women showed a strikingly lower suppressor activity.

ATP-Induced Inflammation Drives Tissue-Resident Th17 Cells in Metabolically Unhealthy Obesity

Obesity-induced inflammation is conducted by a metabolic pathway, which eventually causes activation of specialized immune cells and leads to an unresolved inflammatory response within the tissue. For this reason, it is critically important to determine how hypertrophic fat tissue alters T cell balance to drive inflammation. In this study, we identify the purinergic signaling as a novel mechanism driving the adaptive Th17 response in human visceral adipose tissue (VAT) of metabolically unhealthy obese patients. We demonstrate that ATP acting via the P2X7 receptor pathway promotes a Th17 polarizing microenvironment with high levels of IL-1β, IL-6, and IL-17 in VAT explants from lean donors. Moreover, in vitro blockade of the P2X7 receptor abrogates the levels of these cytokines. These findings are consistent with a greater frequency of Th17 cells in tissue from metabolically unhealthy obese donors, revealed not only by the presence of a baseline Th17-promoting milieu, but also by the higher expression of steadily recognized Th17 markers, such as RORC, IL-17 cytokine, and IL-23R, in comparison with metabolically healthy obese and lean donors. In addition, we demonstrate that CD39 expression on CD4+ effector T cells represents a novel Th17 marker in the inflamed VAT, which also confers protection against ATP-induced cell death. The manipulation of the purinergic signaling might represent a new therapeutic target to shift the CD4+ T cell balance under inflammatory conditions.

Host response to respiratory syncytial virus infection.

Purpose of review Respiratory syncytial virus (RSV) infection is the leading cause of bronchiolitis and hospitalization in young infants and causes 100 000–200 000 deaths annually. There is still no licensed vaccine against RSV infection and the therapeutic options are mainly supportive. Despite almost six decades of research, important knowledge gaps remain with respect to the characterization of immune mechanisms responsible for protection and pathogenesis, as well as to the identification of risk factors that predict the severity of infection. Recent findings Observations made in mouse models and young children suggest that the early innate immune response plays a major role in the pathogenesis of bronchiolitis due to RSV infection. Recent studies have improved our understanding of the role of the adaptive immune response mediated by TH1, TH2, TH17, regulatory T cells, and CD8+ T cells in the pathogenesis and resolution of RSV infection. Moreover, investigations performed in the last years have made important contributions to our knowledge of the immune response in young children, the principal risk group for severe disease. Summary A comprehensive understanding of how the protective and deleterious immune response during the course of RSV infection is induced in young children remains a challenge over the coming years.

Regulatory and effector T-cells are differentially modulated by Dexamethasone☆

It is assumed that the ratio between effector T cells (Teff) and regulatory T cells (Tregs) controls the immune reactivity within the T-cell compartment. The purpose of this study was to investigate if Dexamethasone (Dex) affects Teff and Tregs subsets. Dex induced on Tregs a dose and time-dependent apoptosis which resulted in a relative increase of Teff. After TCR activation, Dex induced a strong proliferative inhibition of Teff, but a weaker proliferative inhibition on Tregs. These effects were modulated by IL-2, which not only restored the proliferative response, but also prevented Dex-induced apoptosis. The highest dose of IL-2 prevented apoptosis on all FOXP3+CD4+ T cells. Meanwhile, the lowest dose only rescued activated Tregs (aTregs), probably related to their CD25 higher expression. Because Dex did not affect the suppressor capacity of aTregs either, our results support the notion that under Dex treatment, the regulatory T-cell compartment maintains its homeostasis.

Depletion of Circulating Regulatory T Cells during Severe Respiratory Syncytial Virus Infection in Young Children

Fil: Raiden, Silvina Claudia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Ninos Pedro Elizalde (ex Casa Cuna); Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clinicas General San Martin; Argentina

Mechanisms involved in the expansion of Tregs during pregnancy: role of IL-2/STAT5 signalling

Several studies have reported that the fine-tuning of regulatory T cells (Tregs) is required for a successful pregnancy and for the control of autoimmune diseases. Here, we review the mechanisms that control the expansion of Tregs, based on insights obtained from the study of women suffering unsuccessful pregnancies and on recent data from patients with autoimmune diseases or with chronic viral infections such as HCV. In particular, we review the role of endocrine factors and IL-2/STAT5 signalling in the impaired expansion of Tregs.

Analysis of Suppressor and Non-Suppressor FOXP3+ T Cells in HIV-1-Infected Patients

Recently, it was shown that peripheral blood FOXP3+CD4+ T cells are composed of three phenotypic and functionally distinct subpopulations. Two of them having in vitro suppressive effects were characterized as resting Treg cells (rTregs) and activated Treg cells (aTregs). A third subset, identified as FOXP3+ non-Tregs, does not display any suppressor activity and produce high levels of Th1 and Th17 cytokines upon stimulation. In the present study we focus on the characteristics of these three subsets of FOXP3+CD4+ T cells in untreated HIV-1-infected patients. We found that the absolute counts of rTregs, aTregs and FOXP3+ non-Tregs were reduced in HIV-1 patients compared with healthy donors. The relative frequency of rTregs and aTregs was similar in HIV-1 patients and healthy donors, while the frequency of FOXP3+ non-Tregs was significantly higher in HIV-1 patients, reaching a maximum in those patients with the lower values of CD4 counts. Contrasting with the observations made in FOXP3- CD4+ T cells, we did not find a negative correlation between the number of rTregs, aTregs or FOXP3+ non-Tregs and virus load. Studies performed with either whole PBMCs or sorted aTregs and FOXP3+ non-Tregs cells showed that these two populations of FOXP3+ T cells were highly permissive to HIV-1 infection. Upon infection, FOXP3+ non-Tregs markedly down-regulates its capacity to produce Th1 and Th17 cytokines, however, they retain the ability to produce substantial amounts of Th2 cytokines. This suggests that FOXP3+ non-Tregs might contribute to the polarization of CD4+ T cells into a Th2 profile, predictive of a poor outcome of HIV-1-infected patients.