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A key issue in mammalian immunology is how CD4 + CD25 + Foxp3 + regulatory T cells (T reg cells) suppress immune responses. Here we show that T reg cells induced apoptosis of effector CD4 + T cells in vitro and in vivo in a mouse model of inflammatory bowel disease. T reg cells did not affect the early activation or proliferation of effector CD4 + T cells. Cytokines that signal through the common γ-chain suppressed T reg cell–induced apoptosis. T reg cell–induced effector CD4 + T cell death required the proapoptotic protein Bim, and effector CD4 + T cells incubated with T reg cells showed less activation of the prosurvival kinase Akt and less phosphorylation of the proapoptotic protein Bad. Thus, cytokine deprivation–induced apoptosis is a prominent mechanism by which T reg cells inhibit effector T cell responses.

Signaling lymphocytic activation molecule family 3 (SLAMF3/Ly9) is a coregulatory molecule implicated in T-cell activation and differentiation. Systemic lupus erythematosus (SLE) is characterized by aberrant T-cell activation and compromised IL-2 production, leading to abnormal regulatory T-cell (Treg) development/function. Here we show that SLAMF3 functions as a costimulator on CD4⁺ T cells and influences IL-2 response and T helper cell differentiation. SLAMF3 ligation promotes T-cell responses to IL-2 via up-regulation of CD25 in a small mothers against decapentaplegic homolog 3 (Smad3)-dependent mechanism. This augments the activation of the IL-2/IL-2R/STAT5 pathway and enhances cell proliferation in response to exogenous IL-2. SLAMF3 costimulation promotes Treg differentiation from naïve CD4⁺ T cells. Ligation of SLAMF3 receptors on SLE CD4⁺ T cells restores IL-2 responses to levels comparable to those seen in healthy controls and promotes functional Treg generation. Taken together, our results suggest that SLAMF3 acts as potential therapeutic target in SLE patients by augmenting sensitivity to IL-2.

Immune responses play an important role in the pathogenesis of polycystic ovary syndrome (PCOS). However, the characteristics of T lymphocyte subsets in PCOS remain insufficiently understood. In this study, lymphocytes of follicular fluid (FF) were obtained from oocyte retrieval before in-vitro fertilization (IVF) in infertile women with or without PCOS. The levels of cluster of differentiation 25 (CD25), CD69, programmed death 1 (PD-1), interferon-γ (IFN-γ), interleukin 17A (IL-17A) and IL-10 in T lymphocytes were determined by flow cytometry. Our results showed that the percentage of FF CD8 + T cells was significantly decreased in infertile patients with PCOS ( P  < 0.05). Furthermore, the levels of CD69 and IFN-γ were significantly decreased and the level of PD-1 was increased in both CD4 + and CD8 + T cells from infertile patients with PCOS ( P  < 0.05). Moreover, the expression of PD-1 on CD4 + or CD8 + T cells was positively correlated with the estradiol (E2) levels in the serum and reversely correlated with the expression of IFN-γ in CD4 + or CD8 + T cells in infertile patients with PCOS. These results suggested that T cell dysfunction may be involved in the pathogenesis of PCOS.

ObjectivesRandomised-controlled trials have recently proven the efficacy of the interleukin (IL)-6 receptor antagonist tocilizumab (TCZ) in giant cell arteritis (GCA). However, the mechanism of action of IL-6 blockade in this disease is unknown. Moreover, the role of regulatory T (Treg) cells in the pathogenesis of GCA remains underexplored. Given the plasticity of Tregs and the importance of IL-6 in their biology, we hypothesised that TCZ might modulate the Treg response in GCA. We therefore characterised the Treg compartment of patients with GCA treated with TCZ.MethodsWe classified 41 patients with GCA into three groups: active disease (aGCA, n=11), disease remission on corticosteroids (rGCA-CS, n=19) and disease remission on TCZ (rGCA-TCZ, n=11). Healthy controls (HCs) were included for comparison. We determined the frequency, phenotype and function of peripheral blood Tregs.ResultsPatients with aGCA demonstrated a hypoproliferating Treg compartment enriched in IL-17-secreting Tregs (IL-17+Tregs). Tregs in patients with aGCA disproportionally expressed a hypofunctional isoform of Foxp3 that lacks exon 2 (Foxp3Δ2). Foxp3Δ2-expressing Tregs coexpressed CD161, a marker commonly associated with the Th17 linage, significantly more often than full-length Foxp3-expressing Tregs. Compared with those of HCs, GCA-derived Tregs demonstrated impaired suppressor capacity. Treatment with TCZ, in contrast to CS therapy, corrected the Treg abnormalities observed in aGCA. In addition, TCZ treatment increased the numbers of activated Tregs (CD45RA−Foxp3high) and the Treg expression of markers of trafficking (CCR4) and terminal differentiation (CTLA-4).ConclusionsTCZ may exert its therapeutic effects in GCA by increasing the proliferation and activation of Tregs, and by reverting the pathogenic Treg phenotype seen during active disease.

CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs) are potent suppressors of the adaptive immune system, but their effects on innate immune cells are less well known. Here we demonstrate a previously uncharacterized function of Tregs, namely their ability to steer monocyte differentiation toward alternatively activated macrophages (AAM). AAM are cells with strong antiinflammatory potential involved in immune regulation, tissue remodeling, parasite killing, and tumor promotion. We show that, after coculture with Tregs, monocytes/macrophages display typical features of AAM, including up-regulated expression of CD206 (macrophage mannose receptor) and CD163 (hemoglobin scavenger receptor), an increased production of CCL18, and an enhanced phagocytic capacity. In addition, the monocytes/macrophages have reduced expression of HLA-DR and a strongly reduced capacity to respond to LPS in terms of proinflammatory mediator production (IL-1β, IL-6, IL-8, MIP-1α, TNF-α), NFκB activation, and tyrosine phosphorylation. Mechanistic studies reveal that CD4⁺CD25⁺CD127lowFoxp3⁺ Tregs produce IL-10, IL-4, and IL-13 and that these cytokines are the critical factors involved in the suppression of the proinflammatory cytokine response. In contrast, the Treg-mediated induction of CD206 is entirely cytokine-independent, whereas the up-regulation of CD163, CCL18, and phagocytosis are (partly) dependent on IL-10 but not on IL-4/IL-13. Together these data demonstrate a previously unrecognized function of CD4⁺CD25⁺Foxp3⁺ Tregs, namely their ability to induce alternative activation of monocytes/macrophages. Moreover, the data suggest that the Treg-mediated induction of AAM partly involves a novel, cytokine-independent pathway.

Myeloid‐derived suppressor cells (MDSC) represent a heterogeneous population and have the potential to suppress immune responses via diverse mechanisms. In recent studies, a new subset of MDSC was identified by the markers CD14+ and HLA‐DR− in the peripheral blood from cancer patients. In this study, we investigated the proportions and characteristics of CD14+ HLA‐DR− cells in patients with squamous cell carcinoma of the head and neck (SCCHN). As expected, the percentage of CD14+ HLA‐DR− cells was significantly elevated in patients relative to healthy donors and the sorted CD14+ HLA‐DR− cells were able to suppress effectively both the proliferation and IFN‐γ production of anti‐CD3/anti‐CD28 stimulated T cells, suggesting that CD14+ HLA‐DR− cells in patients with SCCHN contribute to the immune suppressive status. Furthermore, CD14+ HLA‐DR− cells revealed a higher level of CD86 and PD‐L1 expression and transforming growth factor (TGF)‐β production than CD14+ HLA‐DR+ cells. Addition of anti‐CD86 mAb, anti‐PD‐L1 mAb and anti‐TGF‐β mAb partially restored T‐cell proliferation and IFN‐γ production, respectively, indicating that the suppressive effects of CD14+ HLA‐DR− cells appear to be mediated by various molecules, including coinhibitory molecules and cytokines. Our data suggest that CD14+ HLA‐DR− cells act as potent immunosuppressive cells and particularly contribute to tumor escape from the host immune system in patients with SCCHN. (Cancer Sci 2012; 103: 976–983)

Purpose Cell therapy may become an option for lung injury treatment. However, no data are available on the alveolar presence and time course of CD4+ CD25 + Foxp3 + T-regulatory lymphocyte cells (Tregs) in acute respiratory distress syndrome (ARDS). Accordingly, we (1) measured the ratio of CD4 + CD25 + Foxp3 + Tregs to all (CD4+) lymphocytes in the bronchoalveolar lavage (BAL) of ARDS patients and of control subjects without lung disease and (2) assessed their impact on 30-day mortality. Methods In a prospective study, the ratios of CD4 + CD25 + Foxp3 + T-regulatory cells to all CD4+ cells were measured (FACS) within 24 h of the patients’ ICU referral in the BAL and in the blood of 47 patients with ARDS (32 males, 15 females; mean age 44 years ±13) as well as in 8 controls undergoing elective abdominal surgery (5 men, 3 women; mean age 49 years ±4). BAL concentrations of several cytokines were also measured in ARDS patients. Results Tregs were detected in the BAL of control subjects and ARDS patients. However, the mean ratio of Tregs to all CD4+ lymphocytes was threefold greater in ARDS non-survivors (16.5 %; p  = 0.025) and almost twofold greater in ARDS survivors (9.0 %; p  = 0.015) compared to controls (5.9 %). Multivariate Cox regression analysis revealed the ratio of CD4 + CD25 + Foxp3 + T-regulatory lymphocytes to all CD4+ lymphocytes in the BAL to be an important and independent prognostic factor for 30-day survival (HR 6.5; 95 % CI, 1.7–25; p  = 0.006). Conclusion An increased T-regulatory cell ratio in the admission BAL of patients with ARDS is an important and independent risk factor for 30-day mortality.

Background. Conventional regulatory T cells (Tregs) can suppress human immunodeficiency virus type 1 (HIVl)-specific immune responses but cannot control immune activation in primary HIV infection. Here, we characterized Treg subsets, using recently defined phenotypic delineation, and analyzed the relative contribution of cell subsets to the production of immunosuppressive cytokines in primary HIV infection. Methods. In a longitudinal prospective study, ex vivo phenotyping of fresh peripheral blood mononuclear cells from patients with primary HIV infection was performed at baseline and month 6 of follow-up to characterize Treg subsets, immune activation, and cytokine production in isolated CD4⁺ T cells. Results. The frequency of CD4⁺CD25⁺CD127low Tregs and the distribution between the naive, memory, and activated/memory Treg subsets was similar in patients and healthy donors. However, Tregs from patients with primary HIV infection showed peculiar phenotypic profiles, such as elevated FoxP3, ICOS, and CTLA-4 expression, with CTLA-4 expression strikingly increased in all Treg subsets both at baseline and month 6 of follow-up. The great majority of interleukin 10 (IL-10)-producing CD4⁺ T cells were FoxP3 neg (ie, Tr1-like cells). In contrast to conventional Tregs, Trl-like cells were inversely correlated with immune activation and not associated with lower effector T-cell responses. Conclusion. FoxP3neg Tr1-like cells—major contributors to IL-10 production—may have a beneficial role by controlling immune activation in early HIV infection.

Human regulatory T (Treg) cells play a central role in controlling allergic inflammation in the airways. A reduced number of peripheral Treg cells and decreased suppressive function have been previously reported in the pathogenesis of allergic asthma. However, the characteristic role of specific Treg cell subsets and their mechanisms in the pathogenesis of allergic asthma remain unclear. In this study, we examined the proportion of different Treg cell subsets in both healthy subjects and patients with allergic asthma using flow cytometry and single-cell RNA sequencing. The migration function of the cells was compared using cell sorting and Transwell experiments. Furthermore, two allergen-challenged mouse models and a cell transfer experiment were used to examine the role of these Treg subsets. We found that the proportion of CD25 + Foxp3 + CD127 - Treg cells in the peripheral blood of patients with allergic asthma was lower than in those of healthy subjects. Furthermore, the circulating Treg cells expressed lower levels of CCR6 and IL-17 compared with healthy subjects. The chemokine from the airway mucosa, CCL20, was abundantly expressed, and Transwell experiments further proved that this chemokine promoted CCR6 + Treg cell migration in vitro . A mouse model induced by house dust mite (HDM) revealed that the number of CCR6 + Treg cells in the lung tissue increased remarkably. The incidence of allergic asthma may be related to an increase in Treg cells secreting IL-17 in the lung tissue. Recruited CCR6 + Treg cells are likely to differentiate into Th17-like cells under the Th17 environment present in the lungs. IL-17 derived from Th17-like cells could be associated with the pathology of allergic asthma by promoting Th17 responses, thereby favoring HDM-induced asthma exacerbations.

Till now, the management of autoimmune thyroid diseases (AITD) depends on symptomatic treatment and replacement or anti-thyroid therapy. Uncovering the pathophysiologic mechanisms of autoimmunity provides hope for new insights into management. These new treatments aim to modulate the immune reaction and stop the autoimmune process. T regulatory cells (Tregs) are central in antagonising autoimmunity. This study aimed to compare the number of CD4/CD25/FOXP3 T regulatory cells in the different forms of autoimmune thyroid diseases and in the normal population, and to compare the number of CD4 + CD25 + FOXP3 + T regulatory cells between the different forms of AITD, HT, and GD. Also, to investigate the difference in the number of CD4/CD25/FOXP3 T regulatory cells in AITD associated with allergic disorders on one hand and autoimmune thyroid diseases not associated with allergic disorders on the other hand. This study included 18 patients suffering from Hashimoto’s thyroiditis (HT), 15 patients suffering from Graves’ disease (GD); and, for comparison, the Tregs level was measured in 15 healthy control patients. A statistically significant decrease was found regarding CD4/CD25, CD25/FOXP3 percentages and CD4/CD25/FOXP3 absolute number between patients of AITD and the normal population. The absolute number of CD4/CD25/FOXP3 was lower in the GD group than in HT group. Allergic comorbidities do not influence Tregs percentage or their CD4/CD25/FOXP3 absolute number in any of the AITD forms. Tregs may be a potential therapeutic target for AITD.