Cutting edge: activation of NK T cells by CD1d and alpha-galactosylceramide directs conventional T cells to the acquisition of a Th2 phenotype.

NK T cells recognize glycolipid Ags such as alpha-galactosylceramide (alpha-GalCer) presented by the MHC class I-like molecule CD1d. In this paper we have studied the in vivo effects of alpha-GalCer on the generation of adaptive immune responses. Treatment of mice with alpha-GalCer resulted in rapid activation of NK T cells and production of the cytokines IL-4 and IFN-gamma. However, after this initial stimulation, NK T cells became polarized for the production of IL-4. Further, as soon as 6 days after alpha-GalCer injection, a marked increase in serum IgE levels was observed. Administration of alpha-GalCer at the time of priming of mice with protein Ag resulted in the generation of Ag-specific Th2 cells and a profound increase in the production of IgE. Collectively, these findings indicate that alpha-GalCer may be useful for modulating immune responses toward a Th2 phenotype during prophylaxis and therapy.     

Immunological characteristics in the therapy of atopic dermatitis in children with polycomponent vaccine Immunovac BN-4

IgE-mediated reactions linked with the polarization of the immune process towards, mainly, the activation of Th2 lymphocytes which synthesized interleukins, responsible for switching over B lymphocytes to the production of IgE, were found to be the most important mechanism of the pathogenesis of atopic dermatitis (AD). The use of immunomodulating preparations, capable of changing unbalance in the system of Th1/Th2 cells, is one of promising approaches to the complex therapy of AD. Poly-component vaccine Immunovac BN-4 was included into the complex therapy of AD in children, The dynamics of immunological characteristics was studied for the period of 6 months after the end of the course of therapy. A considerable increase in the absolute and relative amount of lymphocytes with markers CD3, CD4, CD16, CD21, CD25, a rise in the levels of IgA, IgG and a decrease in the level of total IgE in the blood serum were established. The inclusion of the polycomponent vaccine into the complex therapy of AD may be recommended.     

Natural killer cells are involved in acute lung immune injury caused by respiratory syncytial virus infection

It is known that respiratory syncytial virus (RSV) is the main cause of bronchiolitis and pneumonia in young children. RSV infection often leads to severe acute lung immunopathology, but the underlying immune mechanisms are not yet fully elucidated. Here, we found that RSV infection induced severe acute lung immune injury and promoted the accumulation and activation of lung natural killer (NK) cells at the early stage of infection in BALB/c mice. Activated lung NK cells highly expressed activating receptors NKG2D and CD27 and became functional NK cells by producing a large amount of gamma interferon (IFN-γ), which was responsible for acute lung immune injury. NK cell depletion significantly attenuated lung immune injury and reduced infiltration of total inflammatory cells and production of IFN-γ in bronchoalveolar lavage fluid (BALF). These data show that NK cells are involved in exacerbating the lung immune injury at the early stage of RSV infection via IFN-γ secretion.     

Compartmental imbalance and aberrant immune function of blood CD123+ (plasmacytoid) and CD11c+ (myeloid) dendritic cells in atopic dermatitis

Atopic dermatitis (AD) is a pruritic, chronically relapsing skin disease in which Th2 cells play a crucial role in cutaneous and extracutaneous immune reactions. In humans, CD11c+CD123- myeloid dendritic cells (mDC) and CD11c-CD123+ plasmacytoid DC (pDC) orchestrate the decision-making process in innate and acquired immunity. Since the number and function of these blood dendritic cell (DC) subsets reportedly reflect the host immune status, we studied the involvement of the DC subsets in the pathogenesis of AD. Patients with AD had an increased DC number and a low mDC:pDC ratio with pDC outnumbering mDC in the peripheral blood compared with normal subjects and psoriasis patients (a Th1 disease model group). The mDC:pDC ratio was correlated with the total serum IgE level, the ratio of IFN-gamma-producing blood cells:IL-4-producing blood cells, and the disease severity. In vitro allogeneic stimulation of naive CD4+ cells with atopic DC showed that the ability of pDC for Th1 induction was superior or comparable to that of mDC. In skin lesions, pDC infiltration was in close association with blood vessels expressing peripheral neural addressins. Therefore, compartmental imbalance and aberrant immune function of the blood DC subsets may deviate the Th1/Th2 differentiation and thus induce protracted allergic responses in AD.     

Impairment of natural killer (NK) cells is an important factor in a weak Th1-like response in irradiated mice

In whole-body-irradiated (WBI) mice, levels of the canonical Th1 cytokine IFN-gamma (IFNG) have been shown to be markedly reduced, resulting in a Th1/Th2 imbalance. In this study, the influence of natural killer (NK) cells on the balance of this Th1/Th2 immune response was evaluated in WBI mice. Although NK cells are one of the types of cells that secreteIFN-gamma, NK cell activity tends to be minimal, even at 7 weeks after irradiation. In NK cell-depleted mice, the levels of Th1-related cytokines were lower than those of the control mice and were correlated with lower IgG2a production and elevated IgE and IgG1 production. These results indicated that NK cells have a crucial role in the final differentiation of Th cells into Th1 cells. The impairment of NK cells in the WBI mice was confirmed by the observation that NK cells from the WBI mice induced a decrease in the generation of IFN-gamma by the NK cell-depleted spleen lymphocytes from normal mice. Also, the WBI mice that received NK cells obtained from the normal mice generated more IgG2a, IL12 and IFN-gamma. Our results indicate that the impairment of NK cells is an important factor in the reduced Th1-like response in irradiated mice.     

Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques

Epidemiological studies suggest the potential importance of an inflammatory component in atherosclerosis and support the hypothesis that immune responses to Ags of pathogens cross-react with homologous host proteins due to molecular mimicry. Protein candidates involved may be the stress-induced proteins known as heat shock proteins (HSP). In this study, we report that atherosclerotic plaques harbor in vivo-activated CD4(+) T cells that recognize the human 60-kDa HSP. Such in vivo-activated 60-kDa HSP-specific T cells are not detectable in the peripheral blood. In patients with positive serology and PCR for Chlamydia pneumoniae DNA, but not in patients negative for both, most of plaque-derived T cells specific for human 60-kDa HSP also recognized the C. pneumoniae 60-kDa HSP. We characterized the submolecular specificity of such 60-kDa HSP-specific plaque-derived T cells and identified both the self- and cross-reactive epitopes of that autoantigen. On challenge with human 60-kDa HSP, most of the plaque-derived T cells expressed Th type 1 functions, including cytotoxicity and help for monocyte tissue factor production. We suggest that arterial endothelial cells, undergoing classical atherosclerosis risk factors and conditioned by Th type 1 cytokines, express self 60-kDa HSP, which becomes target for both autoreactive T cells and cross-reactive T cells to microbial 60-kDa HSP via a mechanism of molecular mimicry. This hypothesis is in agreement with the notion that immunization with HSP exacerbates atherosclerosis, whereas immunosuppression and T cell depletion prevent the formation of arteriosclerotic lesions in experimental animals.     

Natural killer cells in perinatally HIV-1-infected children exhibit less degranulation compared to HIV-1-exposed uninfected children and their expression of KIR2DL3, NKG2C, and NKp46 correlates with disease severity

NK cells play an integral role in the innate immune response by targeting virally infected and transformed cells with direct killing and providing help to adaptive responses through cytokine secretion. Whereas recent studies have focused on NK cells in HIV-1-infected adults, the role of NK cells in perinatally HIV-1-infected children is less studied. Using multiparametric flow cytometric analysis, we assessed the number, phenotype, and function of NK cell subsets in the peripheral blood of perinatally HIV-1-infected children on highly active antiretroviral therapy and compared them to perinatally exposed but uninfected children. We observed an increased frequency of NK cells expressing inhibitory killer Ig-like receptors in infected children. This difference existed despite comparable levels of total NK cells and NK cell subpopulations between the two groups. Additionally, NK cell subsets from infected children expressed, with and without stimulation, significantly lower levels of the degranulation marker CD107, which correlates with NK cell cytotoxicity. Lastly, increased expression of KIR2DL3, NKG2C, and NKp46 on NK cells correlated with decreased CD4+ T-lymphocyte percentage, an indicator of disease severity in HIV-1- infected children. Taken together, these results show that HIV-1-infected children retain a large population of cytotoxically dysfunctional NK cells relative to perinatally exposed uninfected children. This reduced function appears concurrently with distinct NK cell surface receptor expression and is associated with a loss of CD4+ T cells. This finding suggests that NK cells may have an important role in HIV-1 disease pathogenesis in HIV-1-infected children.     

A novel serum protein that is selectively produced by cytotoxic lymphocytes

Cytotoxic lymphocytes such as CTL and NK cells play principal roles in the host defense mechanisms. Monitoring these effector cells in vivo is helpful to understand the immune responses in disorders such as cancer and infectious diseases. In this study, we identified a novel secretory protein, killer-specific secretory protein of 37 kDa (Ksp37), as a Th1-specific protein by a subtractive cloning method between human Th1 and Th2 cells. In peripheral blood leukocytes, Ksp37 expression was limited to Th1-type CD4(+) T cells, effector CD8(+) T cells, gammadelta T cells, and CD16(+) NK cells. Most of these Ksp37-expressing cells coexpressed perforin, indicating that Ksp37 is selectively and commonly expressed in the lymphocytes that have cytotoxic potential. Ksp37 was released at constant rate from both unstimulated and stimulated PBMCs in vitro and also detected in normal human sera. In healthy individuals, serum Ksp37 levels were significantly higher in children (mean +/- SD; 984 +/- 365 ng/ml for age 0-9) than in adults (441 +/- 135 ng/ml for age 20-99), consistent with reported differences in the absolute counts of blood T and NK cells between children and adults. In patients with infectious mononucleosis, transient elevation of serum Ksp37 levels was observed during the early acute phase of primary EBV infection. These results suggest that Ksp37 may be involved in an essential process of cytotoxic lymphocyte-mediated immunity and that Ksp37 may also have clinical value as a new type of serum indicator for monitoring cytotoxic lymphocytes in vivo.     

NK3-like NK cells are involved in protective effect of polyinosinic-polycytidylic acid on type 1 diabetes in nonobese diabetic mice

Type 1 diabetes in NOD mice is characterized by the uncontrolled Th1 immune responses and deficiency of regulatory or suppressor cells. Previous study has shown that NOD mice treated with polyinosinic-polycytidylic acid (poly(I:C)) have a markedly reduced incidence of diabetes, but the underlying mechanisms remain unclear. In this study, we report that the prevention of diabetes by poly(I:C) is associated with the formation of Th2-enriched environment in spleen and pancreas. We further show that the prevention of diabetes and the formation of Th2-enriched environment depend on the presence of NK cells. Long-term poly(I:C)-treated NK cells exhibit a NK3-like phenotype, and are involved in the induction of Th2 bias of spleen cells in response to islet autoantigens via TGF-beta-dependent manner. Therefore, NK cells mediate the protective effect of poly(I:C) possibly through the promotion of Th2 bias of immune responses. These findings suggest that NK cells can participate in the regulation of autoimmune diabetes.     

Suppression of skin lesions by transdermal application of CpG-oligodeoxynucleotides in NC/Nga mice, a model of human atopic dermatitis

Atopic dermatitis (AD) is a pruritic inflammatory skin disease characterized by an elevation of the total IgE level in plasma, the infiltration of mast cells and eosinophils, and the expression of cytokines by Th2 cells. NC/Nga mice kept in conventional conditions are known to develop skin lesions resembling human AD. We examined in this study the alterations of immune response in NC/Nga mice kept in conventional conditions, following transdermal application of CpG-oligodeoxynucleotides (ODN), which plays a critical role in immunity via the augmentation of Th1-type and suppression of Th2-type responses. CpG-ODN remarkably changed the immune response from type Th2 to Th1 as determined from cytokine mRNA and Ab levels. The serum IgE level was decreased and the expression of IgG2a was up-regulated. The application of CpG-ODN to the skin also decreased inflammatory infiltration of mast cells, and suppression in the skin lesions was observed. Furthermore, the generation of regulatory T cells, which are considered immune suppressive T cells, was observed in the skin on treatment with CpG-ODN. These results suggested CpG-ODN is effective for immunotherapy in patients with AD, which is characterized by Th2-dominated inflammation.     

Genetic background influences natural killer cell activation during bacterial peritonitis in mice, and is interleukin 12 and interleukin 18 independent

Some mouse strains produce strong pro-inflammatory, T-helper (Th)1 responses (e.g. C57BL/6), or strong anti-inflammatory, Th2 responses (e.g. BALB/c). The exact mechanisms for development of distinct immune responses to infection are not completely understood, although cytokines such as interleukin (IL)-12, IL-18 and IL-4 are known to play roles. Natural killer T (NKT)/natural killer (NK) cells are important regulators of immune responses in infection and non-infection models, and NKT/NK activation is also regulated by IL-12 and IL-18 in many models. We investigated the role of IL-12/IL-18 in NKT/NK activation in murine bacterial peritonitis, as well as differential NKT and NK cell activation in C57BL/6 and BALB/c mice. No differences in NKT or NK cell activation or intracellular interferon (IFN)-gamma were determined between mice given control, anti-IL-12 or anti-IL-18 antibodies or in NKT/NK cell activation in STAT4-/- mice (deficient in IL-12 signaling) or wild type controls. However, there were significant differences in the activation of NKT and NK cells between C57BL/6 mice and BALB/c mice, with NKT/NK cytokine production following Th1 or Th2 lines dependent on strain. This suggests a role for NKT and NK cell activation in the development of Th1 and Th2 responses during bacterial infection independently of IL-12 or IL-18.     

A critical role for antigen-specific Th1 cells in acute liver injury in mice.

A novel liver injury model was established in mice by targeting of OVA-containing liposomes into the liver, followed by adoptive transfer of OVA-specific Th1 cells. Combined treatment of mice with OVA-containing liposomes and Th1 cell transfer caused an increase in serum transaminase activity that was paralleled with an elevation of serum IFN-gamma levels. In sharp contrast, OVA-specific Th2 cell transfer resulted in an increase of serum IL-4 levels, but did not induce liver injury. Neither NK, NK T, nor CD8+ T cells were required for the Th1-induced liver injury. The liver injury was blocked by anti-IFN-gamma mAb and anti-TNF-alpha mAb, but not by anti-Fas ligand mAb. The Fas/Fas ligand independency was also demonstrated using Fas-deficient lpr mice. These findings indicate that Th1 cells are the major effector cells in acute liver injury.     

Natural killer cells control a T-helper 1 response in patients with Behçet's disease

Introduction

Behçet's disease (BD) is a multisystem inflammatory disorder, in which a T-helper 1 (Th1)-polarized immune response plays a major role in the pathogenic process. We evaluated the regulatory role of natural killer (NK) cells in Th1-biased immune responses in patients with BD.

Methods

We studied 47 patients with BD, including 10 with active disease (aBD) and 37 with inactive disease (iBD), and 29 healthy controls. The activation status and cytotoxic activity of NK cells were examined by flow cytometry. The levels of mRNAs for immune modulatory and cytotoxic molecules in NK cells were determined by quantitative PCR. The IL-12 signal strength in NK cells was determined by assessing the phosphorylation state of its downstream component, signal transducer and activator of transduction 4, by immunoblotting. Finally, NK cells' ability to modulate the Th1 response was evaluated by co-culturing NK cells and T cells without cell contact.

Results

CD69⁺-activated NK cells were significantly increased in aBD compared with iBD or control samples, although their cytotoxic activities were similar. The iBD NK cells showed downregulated IL-12 receptor β₂ mRNA levels compared with aBD or control NK cells. The increased IL-13 expression was detected in a subset of BD patients: most of them had iBD. The IL-13 expression level in iBD patients was significantly higher than the level in controls, but was not statistically different compared with the level in aBD patients. The gene expression profile in iBD patients was consistent with the NK type 2 phenotype, and the shift to NK type 2 was associated with disease remission. NK cells from iBD patients showed impaired IL-12-induced signal transducer and activator of transduction 4 phosphorylation. Finally, iBD, but not control, NK cells suppressed IFNγ expression by aBD-derived CD4⁺ T cells in vitro.

Conclusions

NK cells may control disease flare/remission in BD patients via NK type 2-mediated modulation of the Th1 response.

     

Cellular immune responses in children and adults receiving inactivated or live attenuated influenza vaccines

The patterns of cellular immune responses induced by live attenuated influenza vaccine (LAIV) versus those of the trivalent inactivated influenza vaccine (TIV) have not been studied extensively, especially in children. The goals of this study were to evaluate the effects of TIV and LAIV immunization on cellular immunity to live influenza A virus in children and adults and to explore factors associated with variations in responses to influenza vaccines among individuals. A gamma interferon (IFN-gamma) flow cytometry assay was used to measure IFN-gamma-producing (IFN-gamma+) NK and T cells in peripheral blood mononuclear cell cultures stimulated with a live influenza A virus strain before and after LAIV or TIV immunization of children and adults. The mean percentages of influenza A virus-specific IFN-gamma+ CD4 and CD8 T cells increased significantly after LAIV, but not TIV, immunization in children aged 5 to 9 years. No increases in the mean levels of influenza A virus-reactive IFN-gamma+ T cells and NK cells were observed in adults given LAIV or TIV. TIV induced a significant increase in influenza A virus-reactive T cells in 6-month- to 4-year-old children; LAIV was not evaluated in this age group. The postvaccination changes (n-fold) in the percentages of influenza A virus-reactive IFN-gamma+ T and NK cells in adults were highly variable and correlated inversely with the prevaccination percentages, in particular with that of the CD56(dim) NK cell subset. In conclusion, our findings identify age, type of vaccine, and prevaccination levels of immune reactivity to influenza A virus as factors significantly associated with the magnitude of cellular immune responses to influenza vaccines.     

Circulating Mitochondrial DAMPs Are Not Effective Inducers of Proteinuria and Kidney Injury in Rodents

Mitochondria in eukaryotic cells are derived from bacteria in evolution. Like bacteria, mitochondria contain DNA with unmethylated CpG motifs and formyl peptides, both of which have recently been shown to be damage associated molecular patterns (DAMPs) and induce immune response and cell injury. Based on the facts that circulating mitochondrial DAMPs (mtDAMPs) are increased in the patients of trauma or burn injury who also have proteinuria, that mtDAMPs can activate immune cells which in turn secrete glomerular permeability factors, that renal intrinsic cells express a variety of DAMP receptors, and that mtDAMPs can directly increase endothelial cell permeability in vitro, we hypothesized that mtDAMPs may be novel circulating factors inducing proteinuria and kidney injury. We tested this hypothesis by directly injecting mtDAMPs into rodents and examining urinary protein and kidney histology. We prepared mtDAMP samples, including mitochondrial DNA (mtDNA) and mitochondrial debris (MTD), from rodent liver. In mice, injection of mtDNA for 20 μg/ml initial concentration in circulation (much higher than the clinical range), did not cause any renal manifestations. However, an increased dose leading to 45 μg/ml initial concentration in circulation resulted in a transient, slight increase in urinary albumin. In rats, MTD injection resulting in 450 μg/ml initial concentration of MTD protein in circulation, which was much higher than the clinical range, caused mild, transient proteinuria and lung lesions. Multiple injections of such large amount of either mtDNA or MTD into rodents on 3 consecutive days also failed in inducing proteinuria and kidney injury. In summary, clinical levels of circulating mtDAMPs do not induce proteinuria and clinically irrelevant high levels of mtDAMPs cause only a transient and slight increase in urinary protein in rodents, suggesting that circulating mtDAMPs may not be responsible for the proteinuria and kidney injury in patients with trauma, burn injury, and other diseases.     

Infection of mice with Mycobacterium bovis-BCG induces both Th1 and Th2 immune responses in the absence of interferon-gamma signalling.

A murine pulmonary infection model using Mycobacterium bovis-BCG was used to study the development of Th1 and Th2 type responses in mice lacking a functional IFN-gamma receptor (IFN-gamma R-/-). Strikingly, the IFN-gamma R-/- mice maintained the Th1 response and developed a profound M. bovis-BCG, specific Th2 type immune response characterized by IL-5-producing CD4+ T cells, eosinophil infiltration of granulomas, and significantly elevated serum IgE levels. The increase in IL-5 production and eosinophil recruitment into the lung could be detected within the first 1-2 weeks of infection, indicating that the Th2 response was not due to greatly enhanced bacterial numbers observed later in infection. These results clearly indicate that IFN-gamma acts during M. bovis-BCG infection to suppress the development of Th2 immune responses. Furthermore, they demonstrate that IFN-gamma is not a necessary cofactor in the development of Th1 type cells secreting IFN-gamma. In conclusion, these data demonstrate that IFN-gamma plays a major role in suppressing a potentially disease-promoting Th2 immune response during mycobacterial infections.     

隐球菌性脑膜炎患者外周血中Th9和Th17细胞水平变化及意义

目的：比较初发隐球菌性脑膜炎患者治疗前后与健康对照人群外周血 CD4＋ T 细胞中 Th9和 Th17细胞的比值,探讨 Th9和 Th17细胞在隐球菌性脑膜炎发病机制中的作用。方法选取初发未经治疗隐球菌性脑膜炎患者及健康对照各12例,抽取隐球菌性脑膜炎患者治疗前和治疗后3周及健康对照的外周血,分离外周血单核细胞,应用流式细胞仪检测技术对3组病例外周血 CD4＋ T 细胞中 Th9和 Th17的比值进行比较。结果与健康对照相比,隐球菌性脑膜炎患者治疗前Th17表达下调,差异有统计学意义;在治疗好转患者中,治疗后 Th17表达显著上调,与治疗前及健康对照相比差异均有统计学意义。Th9在治疗前与健康对照相比无差异,在治疗后隐球菌性脑膜炎患者中表达上调。结论 Th17免疫途径是隐球菌性脑膜炎患者抵御隐球菌感染的重要免疫机制,隐球菌性脑膜炎发病及治疗拮抗可能与 Th17缺乏有关。     

Indirect IL-4 pathway in type 1 immunity.

Recall Ag-specific IL-4 was detected in the spleen and in the blood, but not in lymph nodes of mice in which polarized type 1 immunity was induced. This IL-4 was not produced by T cells, but soluble factors secreted by the recall Ag-activated T cells, including IL-3, triggered cells of the innate immune system, primarily mast cells, to secrete IL-4. This notion has profound implications for immunodiagnostics: the detection of apparently recall Ag-specific IL-4 does not necessarily reflect the presence of Th2 or Th0 memory T cells with long-term cytokine commitment as is of interest for assessing adoptive immunity. We found that in vivo the indirect IL-4 pathway did not suffice to trigger IgE isotype switching, but promoted IgG1 production and inhibited type 1 T cell differentiation. Therefore, the indirect IL-4 pathway can explain partial type 2 immune response phenotypes in vivo in face of unipolar Th1 T cell immunity. The representation of mast cells in different tissues may explain why immune responses in certain organs are more type 2 biased. Therefore, the indirect pathway of IL-4 production represents a novel type of interaction between the innate and the adoptive immune system that can contribute to the outcome of host defense and immune pathology.     

Modulation of ongoing human immunoglobulin synthesis by natural killer cells

Freshly separated human NK cells (NKH-1+) inhibited IgE synthesis from IgE myeloma U266/AF-10 as much as 70% whereas they enhanced IgG and IgA synthesis 200 and 500% from the lymphoblastoid cell lines GM-1500 and GM-1056, respectively. The inhibition of IgE synthesis by NK cells was due to a direct cytolytic effect on AF-10. This could be reversed using K562 cells in a cold target competition assay. NK cells also inhibited spontaneous IgE as well as IgG and IgA synthesis from B cells of highly atopic donors. On the other hand the enhancement of Ig secretion by NKH-1+ cells was shown to be mediated by soluble factors released from NK cells. Furthermore when NK cells were preincubated with immune complexes (IgE-IC) constructed of human IgE and mouse IgG1 monoclonal anti-human IgE, inhibition of IgE synthesis was reversed, and in some cases actual enhancement of IgE synthesis was observed, while enhancement of IgG and IgA synthesis was not affected. In contrast to NK cells, T cells depleted of NK cells (T-NK), when activated by IgE-IC, suppressed IgE synthesis in an isotype specific fashion. Thus, NK and T-cell modulation of ongoing Ig synthesis involve distinct mechanisms.     

Filaggrin null mutations are associated with altered circulating Tregs in atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a complex pathogenesis. Although regulatory T cells (Tregs) have previously been studied in AD, their role remains controversial, likely owing to patient heterogeneity. Thus, we recruited adult AD patients and age‐matched healthy controls, and assessed their filaggrin (FLG) genotype, serum IgE level, and eczema area and severity index (EASI). We found increased proportions of all circulating Treg subpopulations in AD patients. Moreover, we show positive correlations between circulating Tregs and serum IgE FLG null mutations limited the expansion of both memory and effector Tregs and enhanced that of recently thymus‐emigrated Tregs. Furthermore, proportions of circulating Th2‐ or Th17‐Tregs but not Th1‐Tregs were increased in AD patients, and accentuated by FLG null mutations, thereby mimicking the immune deviation observed in Th cell populations. Moreover, ICOS⁺ Tregs showed reduced production of interleukin‐10, suggesting impaired immunosuppression in AD. The level of demethylation of FOXP3i1, which reflects the stability of FOXP3 expression, was similar in the blood and skin of AD patients and healthy controls. Overall, these results show that Tregs may participate into AD pathogenesis and that FLG null mutations exert further modifications on specific subpopulations of circulating Tregs.