The autosomal dominant hyper-IgE syndrome (HIES, 'Job's syndrome') is characterized by recurrent and often severe pulmonary infections, pneumatoceles, eczema, staphylococcal abscesses, mucocutaneous candidiasis, and abnormalities of bone and connective tissue1,2. Mutations presumed to underlie HIES have recently been identified in stat3, the gene encoding STAT3 (signal transducer and activator of transcription 3) (refs 3, 4). Although impaired production of interferon-γ and tumour-necrosis factor by T cells5, diminished memory T-cell populations, decreased delayed-type-hypersensitivity responses and decreased in vitro lymphoproliferation in response to specific antigens6 have variably been described, specific immunological abnormalities that can explain the unique susceptibility to particular infections seen in HIES have not yet been defined. Here we show that interleukin (IL)-17 production by T cells is absent in HIES individuals. We observed that ex vivo T cells from subjects with HIES is consistent with a crucial role for STAT3 signalling in the generation of T H 17 cells7-14. T H 17 cells have emerged as an important subset of helper T cells15 that are believed to be critical in the clearance of fungal16 and extracellular bacterial17 infections. Thus, our data suggest that the inability to produce T H 17 cells is a mechanism underlying the susceptibility to the recurrent infections commonly seen in HIES. HHS Public AccessWe studied three groups of subjects: healthy controls with no apparent immunological defects, HIES individuals with defined mutations in stat3, and individuals (termed 'HIESlike') with some combination of elevated IgE, atopic dermatitis, skeletal abnormalities and susceptibility to infection, but without recurrent staphylococcal abscesses or candidiasis or stat3 mutations (Table 1).We observed that IL-17-producing T cells were barely detectable among peripheral blood mononuclear cells (PBMCs) from subjects with HIES on stimulation with staphylococcal enterotoxin B (SEB) (Fig. 1a). The frequency of SEB-induced interferon (IFN)-γ-producing CD4 T cells from PBMCs of subjects with HIES was similar to that of healthy controls, whereas the frequency of cells producing IL-2 and/or tumour-necrosis factor (TNF) was slightly reduced. Fewer of the IFN-γ-producing CD4 T cells from subjects with HIES also produced TNF and/or IL-2 compared with healthy controls (Fig. 1b). IL-17-producing T cells were present in PBMCs from the HIES-like cohort with no mutations in stat3,suggesting that the lack of IL-17 production in HIES has a critical function in susceptibility to the specific infections seen in HIES, and also that elevated serum IgE, atopic dermatitis or low frequency of memory T cells (data not shown) are not independently associated with severe defects in the T H 17 axis (Fig. 1a). The production of IL-21 and IL-22, which have been described as both T H 1 and T H 17 cytokines9,10,18, was not significantly lower in subjects with HIES than in healthy controls. Additionally, among subjects with ...
CD4؉ helper T cells can differentiate into several possible fates including: Th1, Th2, T regulatory, and Th17 cells. Although, cytokine production by non-T cells is an important factor in helper T cell differentiation, a characteristic feature of both Th1 and Th2 lineages is their ability to secrete cytokines that promote their respective differentiation. However, cytokines produced by T cells that help to sustain Th17 cells have not yet been identified. Here we show that IL-21 is a product of Th17 cells, which is induced in a Stat3-dependent manner. Additionally, Stat3 can directly bind the Il21 promoter. IL-21 also induces IL-17 production and expression of the transcription factor, ROR␥t. Furthermore, generation of Th17 cells in the conventional manner is attenuated by blocking IL-21. IL-21 is known to activate Stat3 and its ability to induce Th17 differentiation is abrogated in the absence of Stat3. These data argue that IL-21 serves as an autocrine factor secreted by Th17 cells that promotes or sustains Th17 lineage commitment. CD4ϩ helper T (Th) 3 cells shape immune responses by differentiating into discrete subsets that secrete distinctive cytokines. These patterns are thought to determine the success of the immune system, protect against a particular pathogen, and limit damage to host tissues (1). Until recently, differentiating Th cells were thought to have one of two possible fates defined by their cytokine secretion, namely Th1 and Th2 (2).Intracellular pathogens promote the production of IL-12 by dendritic cells. In concert, with antigen stimulation, IL-12 acting via the transcription factor Stat4, induces the development of a Th1 cell that produces the signature cytokine IFN-␥. Furthermore, IFN-␥ acting via Stat1 also promotes the expression of the transcription factor T-box expressed in T cells (T-bet) which is important for Th1 differentiation (3). In contrast, helminthic pathogens promote the generation Th2 cells that produce the key cytokine IL-4, which activates Stat6 (4). IL-4 has pleiotropic effects, but a key effect is the promotion of Th2 differentiation and antagonism of IFN-␥ production. Thus, a classic feature of Th cells is their production of cytokines that promote their own differentiation and antagonize the differentiation to the other lineage.This simplistic dichotomotous view of T cell differentiation has recently been challenged by the discovery of a new lineage of T cells characterized by the ability to preferentially secrete a proinflammatory cytokine, IL-17 and thus designated Th17 cells (5). These T cells have been implicated in protection from extracellular bacteria (6 -8) and in autoimmune diseases in animals and humans (9, 10).Initially, an IL-12-related cytokine also produced by dendritic cells, IL-23, was thought to be the main driver of Th17 differentiation. However, it was later recognized that IL-23 did not act on naïve CD4ϩ T cells to induce Th17 differentiation. Rather, other inflammatory cytokines produced by dendritic cells, IL-1, and IL-6 in conjunction with trans...
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