Naeun Lee

Effector T cell subsets in systemic lupus erythematosus: update focusing on Th17 cells

Purpose of reviewThe discovery of T helper (Th)17 cells that produce the proinflammatory cytokine IL-17 has substantially advanced our understanding of T-cell biology and autoimmunity. We will review recent findings on effector T cells, in particular Th17 cells, in lupus. Recent findingsStudies reported increased IL-17 levels in the circulation and tissues in human and murine lupus. Patients with systemic lupus erythematosus (SLE or lupus) had an increased frequency of Th17 cells in peripheral blood which correlated with disease activity. However, the frequency of IFN-&ggr;-producing Th1 cells did not change in the same patients, suggesting a selective dysregulation of Th17 cells in SLE. In addition, patients with SLE had an increased frequency of IL-17-producing CD3+CD4−CD8− (double negative) T cells in the peripheral blood and kidneys. Similar findings were noticed in lupus-prone MRL/MP-lpr/lpr (MRL/lpr) mice. A recent study demonstrated that IL-17 could promote B-cell survival and differentiation into antibody-producing cells. This raises the possibility that IL-17 is implicated in the pathogenesis of SLE by promoting humoral immunity against self-antigen. SummaryEmerging data show a body of evidence that IL-17 and Th17 cells may play a role in the pathogenesis of SLE. Further studies are warranted to dissect the mechanism for increased IL-17 production and the therapeutic implication of targeting this cytokine in SLE.

1,25-Dihyroxyvitamin D3 Promotes FOXP3 Expression via Binding to Vitamin D Response Elements in Its Conserved Noncoding Sequence Region

FOXP3-positive regulatory T (Treg) cells are a unique subset of T cells with immune regulatory properties. Treg cells can be induced from non-Treg CD4+ T cells (induced Treg [iTreg] cells) by TCR triggering, IL-2, and TGF-β or retinoic acid. 1,25-Dihyroxyvitamin D3 [1,25(OH)2VD3] affects the functions of immune cells including T cells. 1,25(OH)2VD3 binds the nuclear VD receptor (VDR) that binds target DNA sequences known as the VD response element (VDRE). Although 1,25(OH)2VD3 can promote FOXP3 expression in CD4+ T cells with TCR triggering and IL-2, it is unknown whether this effect of 1,25(OH)2VD3 is mediated through direct binding of VDR to the FOXP3 gene without involving other molecules. Also, it is unclear whether FOXP3 expression in 1,25(OH)2VD3-induced Treg (VD-iTreg) cells is critical for the inhibitory function of these cells. In this study, we demonstrated the presence of VDREs in the intronic conserved noncoding sequence region +1714 to +2554 of the human FOXP3 gene and the enhancement of the FOXP3 promoter activity by such VDREs in response to 1,25(OH)2VD3. Additionally, VD-iTreg cells suppressed the proliferation of target CD4+ T cells and this activity was dependent on FOXP3 expression. These findings suggest that 1,25(OH)2VD3 can affect human immune responses by regulating FOXP3 expression in CD4+ T cells through direct VDR binding to the FOXP3 gene, which is essential for inhibitory function of VD-iTreg cells.

T-Cell Biology in Aging, With a Focus on Lung Disease

T cells are essential for defending hosts against microorganisms and malignancy as well as for regulating the development of immune-mediated inflammatory diseases like autoimmunity. Alterations in T-cell immunity occur with aging, affecting the function and proportions of T-cell subsets. Probably, the most noticeable age-associated change in T-cell immunity is an alteration in the frequency of naive and memory CD4+ and CD8+ T cells. In fact, the frequency of naive CD4+ and CD8+ T cells decreases with aging, whereas the frequency of memory CD4+ and CD8+ T cells increases. Also, changes in T-cell proliferation, cytokine production, memory response, and cytotoxicity as well as in regulatory T-cell number and function have been reported with aging. Such alterations could contribute to the development of infections, malignancies, and inflammatory diseases that rise with aging. Of interest, T cells are closely involved in the development of inflammatory airway and lung diseases including asthma and chronic obstructive pulmonary disease, which are prevalent in the elderly people. In addition, T cells play a major role in defending host against influenza virus infection, a serious medical problem with high morbidity and mortality in the elderly people. Thus, it is conceivable that altered T-cell immunity may account in part for the development of such respiratory problems with aging. Here, we will review the recent advances in T-cell immunity and its alteration with aging and discuss the potential effects of such changes on the lung.

Self Double-Stranded (ds)DNA Induces IL-1β Production from Human Monocytes by Activating NLRP3 Inflammasome in the Presence of Anti–dsDNA Antibodies

The pathogenic hallmark of systemic lupus erythematosus is the autoimmune response against self nuclear Ags, including dsDNA. The increased expression of the proinflammatory cytokine IL-1β has been found in the cutaneous lesion and PBMCs from lupus patients, suggesting a potential involvement of this cytokine in the pathogenesis of lupus. IL-1β is produced primarily by innate immune cells such as monocytes and can promote a Th17 cell response, which is increased in lupus. IL-1β production requires cleaving pro–IL-β into IL-1β by the caspase-1–associated multiprotein complex called inflammasomes. In this study we show that self dsDNA induces IL-1β production from human monocytes dependent on serum or purified IgG containing anti–dsDNA Abs by activating the nucleotide-binding oligomerization domain–like receptor family pyrin domain–containing 3 (NLRP3) inflammasome. Reactive oxygen species (ROS) and K+ efflux were involved in this activation. Knocking down the NLRP3 or inhibiting caspase-1, ROS, and K+ efflux decreased IL-1β production. Supernatants from monocytes treated with a combination of self dsDNA and anti–dsDNA Ab+ serum promoted IL-17 production from CD4+ T cells in an IL-1β–dependent manner. These findings provide new insights in lupus pathogenesis by demonstrating that self dsDNA together with its autoantibodies induces IL-1β production from human monocytes by activating the NLRP3 inflammasome through inducing ROS synthesis and K+ efflux, leading to the increased Th17 cell response.

Age-associated alteration in naive and memory Th17 cell response in humans

Th17 cells produce IL-17 that plays an important role in host defense. However, little is known about whether aging affects human Th17 cells. Here we demonstrated that healthy elderly people (age ≥ 65) had a decreased frequency of IL-17-producing cells in memory CD4(+) T cells compared to healthy young people (age ≤ 40) while both groups had similar frequencies of IFN-γ-producing cells in the same memory cell subset as measured by flow cytometry. In contrast, the healthy elderly had increased differentiation of IL-17-producing effector cells but not IFN-γ-producing cells from naive CD4(+) T cells compared to the healthy young. The results of ELISA also showed similar findings with increased IL-17 production from naive CD4(+) T cells and decreased IL-17 production from memory CD4(+) T cells in the elderly compared to the young. These findings indicate that aging differentially affects naive and memory Th17 cell responses in humans.

U1-Small Nuclear Ribonucleoprotein Activates the NLRP3 Inflammasome in Human Monocytes

The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is a caspase-1–containing cytosolic protein complex that is essential for processing and secretion of IL-1β. The U1-small nuclear ribonucleoprotein (U1-snRNP) that includes U1-small nuclear RNA is a highly conserved intranuclear molecular complex involved in splicing pre-mRNA. Abs against this self nuclear molecule are characteristically found in autoimmune diseases like systemic lupus erythematosus, suggesting a potential role of U1-snRNP in autoimmunity. Although endogenous DNA and microbial nucleic acids are known to activate the inflammasomes, it is unknown whether endogenous RNA-containing U1-snRNP could activate this molecular complex. In this study, we show that U1-snRNP activates the NLRP3 inflammasome in CD14+ human monocytes dependently of anti–U1-snRNP Abs, leading to IL-1β production. Reactive oxygen species and K+ efflux were responsible for this activation. Knocking down the NLRP3 or inhibiting caspase-1 or TLR7/8 pathway decreased IL-1β production from monocytes treated with U1-snRNP in the presence of anti–U1-snRNP Abs. Our findings indicate that endogenous RNA-containing U1-snRNP could be a signal that activates the NLRP3 inflammasome in autoimmune diseases like systemic lupus erythematosus where anti–U1-snRNP Abs are present.

U1-Small Nuclear Ribonucleoprotein Activates the NOD-like Receptor Family, Pyrin Domain-Containing 3 Inflammasome in Human Monocytes

The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is a caspase-1–containing cytosolic protein complex that is essential for processing and secretion of IL-1β. The U1-small nuclear ribonucleoprotein (U1-snRNP) that includes U1-small nuclear RNA is a highly conserved intranuclear molecular complex involved in splicing pre-mRNA. Abs against this self nuclear molecule are characteristically found in autoimmune diseases like systemic lupus erythematosus, suggesting a potential role of U1-snRNP in autoimmunity. Although endogenous DNA and microbial nucleic acids are known to activate the inflammasomes, it is unknown whether endogenous RNA-containing U1-snRNP could activate this molecular complex. In this study, we show that U1-snRNP activates the NLRP3 inflammasome in CD14+ human monocytes dependently of anti–U1-snRNP Abs, leading to IL-1β production. Reactive oxygen species and K+ efflux were responsible for this activation. Knocking down the NLRP3 or inhibiting caspase-1 or TLR7/8 pathway decreased IL-1β production from monocytes treated with U1-snRNP in the presence of anti–U1-snRNP Abs. Our findings indicate that endogenous RNA-containing U1-snRNP could be a signal that activates the NLRP3 inflammasome in autoimmune diseases like systemic lupus erythematosus where anti–U1-snRNP Abs are present.

IL-6 receptor α defines effector memory CD8+ T cells producing Th2 cytokines and expanding in asthma.

RATIONALE Cytokine receptors can be markers defining different T-cell subsets and considered as therapeutic targets. The association of IL-6 and IL-6 receptor α (IL-6Rα) with asthma was reported, suggesting their involvement in asthma. OBJECTIVES To determine whether and how IL-6Rα defines a distinct effector memory (EM) CD8+ T-cell population in health and disease. METHODS EM CD8+ T cells expressing IL-6Rα (IL-6Rα(high)) were identified in human peripheral blood and analyzed for function, gene, and transcription factor expression. The relationship of these cells with asthma was determined using blood and sputum. MEASUREMENTS AND MAIN RESULTS A unique population of IL-6Rα(high) EM CD8+ T cells was found in peripheral blood. These cells that potently proliferated, survived, and produced high levels of the Th2-type cytokines IL-5 and IL-13 had increased levels of GATA3 and decreased levels of T-bet and Blimp-1 in comparison with other EM CD8+ T cells. In fact, GATA3 was required for IL-6Rα expression. Patients with asthma had an increased frequency of IL-6Rα(high) EM CD8+ T cells in peripheral blood compared with healthy control subjects. Also, IL-6Rα(high) EM CD8+ T cells exclusively produced IL-5 and IL-13 in response to asthma-associated respiratory syncytial virus and bacterial superantigens. CONCLUSIONS Human IL-6Rα(high) EM CD8+ T cells is a unique cell subset that may serve as a reservoir for effector CD8+ T cells, particularly the ones producing Th2-type cytokines, and expand in asthma.

Active Hexose Correlated Compound promotes T helper (Th) 17 and 1 cell responses via inducing IL-1β production from monocytes in humans

The differentiation of T helper (Th) cells is critically dependent on cytokine milieu. The innate immune monocytes produce IL-1β which can affect the development of Th17 and Th1 cells that predominantly produce IL-17 and IFN-γ, respectively. Oligosaccharides from microorganisms, crops and mushrooms can stimulate innate immune cells. Active Hexose Correlated Compound (AHCC) that contains a large amount of oligosaccharides is a natural extract prepared from the mycelium of the edible Basidiomycete fungus. This compound is reported to modulate immune responses against pathogens although the mechanisms for this effect are largely unknown. Here we show that AHCC could induce high levels of IL-1β production from human monocytes. Furthermore, AHCC-treated monocytes increased the production of IL-17 and IFN-γ from autologous CD4(+) T cells, which was blocked by adding IL-1 receptor antagonist. These finding provide new insight into how food supplements like AHCC could enhance human immunity by modulating monocytes and Th cells.

Microbiota in T-cell homeostasis and inflammatory diseases.

The etiology of disease pathogenesis can be largely explained by genetic variations and several types of environmental factors. In genetically disease-susceptible individuals, subsequent environmental triggers may induce disease development. The human body is colonized by complex commensal microbes that have co-evolved with the host immune system. With the adaptation to modern lifestyles, its composition has changed depending on host genetics, changes in diet, overuse of antibiotics against infection and elimination of natural enemies through the strengthening of sanitation. In particular, commensal microbiota is necessary in the development, induction and function of T cells to maintain host immune homeostasis. Alterations in the compositional diversity and abundance levels of microbiota, known as dysbiosis, can trigger several types of autoimmune and inflammatory diseases through the imbalance of T-cell subpopulations, such as Th1, Th2, Th17 and Treg cells. Recently, emerging evidence has identified that dysbiosis is involved in the progression of rheumatoid arthritis, type 1 and 2 diabetic mellitus, and asthma, together with dysregulated T-cell subpopulations. In this review, we will focus on understanding the complicated microbiota-T-cell axis between homeostatic and pathogenic conditions and elucidate important insights for the development of novel targets for disease therapy.