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Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4(+) T-cell subsets, regulatory T cells, CD8(+) T cells, B cells, and monocytes. We find that ∼90% of causal variants are non-coding, with ∼60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10-20% directly alter recognizable transcription factor binding motifs. Rather, most non-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.

T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and [...]

The intermediate stages of cell-to-cell spread by L. monocytogenes remain unclear. On the basis of observations with an in vitro infection model, it has been suggested that bacteria-containing protrusions are [...], Efferocytosis, the process by which dying or dead cells are removed by phagocytosis, has an important role in development, tissue homeostasis and innate immunity (1). Efferocytosis is mediated, in part, by receptors that bind to exofacial phosphatidylserine (PS) on cells or cellular debris after loss of plasma membrane asymmetry. Here we show that abacterial pathogen, Listeria monocytogenes, can exploit efferocytosis to promote cell-to-cell spread during infection. These bacteria can escape the phagosome in host cells by using the poreforming toxin listeriolysin O (LLO) and two phospholipase C enzymes (2). Expression of the cell surface protein ActA allows L. monocytogenes to activate host actin regulatory factors and undergo actin-based motility in the cytosol, eventually leading to formation of actin-rich protrusions at the cell surface. Here we show that protrusion formation is associated with plasma membrane damage due to LLO's poreforming activity. LLO also promotes the release of bacteria-containing protrusions from the host cell, generating membrane-derived vesicles with exofacial PS. The PS-binding receptor TIM-4 (encoded by the Timd4 gene) contributes to efficient cell-to-cell spread by L. monocytogenesin macrophages invitroand growth of these bacteria is impaired in [Timd4.sup.-/-] mice. Thus, L. monocytogenes promotes its dissemination in a host by exploiting efferocytosis. Our results indicate that PS-targeted therapeutics may be useful in the fight against infections by L. monocytogenes and other bacteria that use similar strategies of cell-to-cell spread during infection.

[T.sub.H]17 cells (interleukin-17 (IL-17)-producing helper T cells) are highly proinflammatory cells that are critical for clearing extracellular pathogens and for inducing multiple autoimmune diseases (1). IL-23 has a critical role [...]

Effective coordination of the immune system requires careful balancing of distinct pro-inflammatory and regulatory CD[4.sup.+] helper T-cell populations. Among those, pro-inflammatory IL-17 producing [T.sub.H]17 cells have a key role in [...], Despite their importance, the molecular circuits that control the differentiation of naive T cells remain largely unknown. Recent studies that reconstructed regulatory networks in mammalian cells have focused on short-term responses and relied on perturbation-based approaches that cannot be readily applied to primary T cells. Here we combine transcriptional profiling at high temporal resolution, novel computational algorithms, and innovative nanowirebased perturbation tools to systematically derive and experimentally validate a model of the dynamic regulatory network that controls the differentiation of mouse [T.sub.H]17 cells, a proinflammatory T-cell subset that has been implicated in the pathogenesis of multiple autoimmune diseases. The [T.sub.H]17 transcriptional network consists of two self-reinforcing, but mutually antagonistic, modules, with 12 novel regulators, the coupled action of which may be essential for maintaining the balance between [T.sub.H]17 and other CD[4.sup.+] T-cell subsets. Our study identifies and validates 39 regulatory factors, embeds them within a comprehensive temporal network and reveals its organizational principles; it also highlights novel drug targets for controlling [T.sub.H]17 cell differentiation.

[T.sub.H]17 cells have been associated with the pathogenesis of several chronic inflammatory disorders, including rheumatoid arthritis and multiple sclerosis (2,7). To study the cellular and molecular mechanisms that control pathogenicity [...], Interleukin (IL)-17-producing T helper cells ([T.sub.H]17) are a recently identified [CD4.sup.+] T cell subset distinct from T helper type 1 ([T.sub.H]1) and T helper type 2 ([T.sub.H]2) cells (1). [T.sub.H]17 cells can drive antigenspecific autoimmune diseases and are considered the main population of pathogenic T cells driving experimental autoimmune encephalomyelitis (EAE) (2), the mouse model for multiple sclerosis. The factors that are needed for the generation of [T.sub.H]17 cells have been well characterized (3-6). However, where and how the immune system controls [T.sub.H]17 cells in vivo remains unclear. Here, by using a model of tolerance induced by CD3-specific antibody, a model of sepsis and influenza A viral infection (H1N1), we show that pro-inflammatory [T.sub.H]17 cells can be redirected to and controlled in the small intestine. [T.sub.H]17-specific IL-17A secretion induced expression of the chemokine CCL20 in the small intestine, facilitating the migration of these cells specifically to the small intestine via the CCR6/CCL20 axis. Moreover, we found that [T.sub.H]17 cells are controlled by two different mechanisms in the small intestine: first, they are eliminated via the intestinal lumen; second, pro-inflammatory [T.sub.H]17 cells simultaneously acquire a regulatory phenotype with invitro and invivoimmune-suppressive properties (r[T.sub.H]17). These results identify mechanisms limiting [T.sub.H]17 cell pathogenicity and implicate the gastrointestinal tract as a site for control of [T.sub.H]17 cells.

The recent discovery of [CD4.sup.+] T cells characterized by secretion of interleukin (IL)-17 ([T.sub.H]17 cells) and the naturally occurring regulatory [FOXP3.sup.+] CD4 T cell ([nT.sub.reg]) has had a major impact [...]

T helper ([T.sub.H]) cells constitute an important arm of the adaptive immune system because they coordinate defence against specific pathogens, and their unique cytokines and effector functions mediate different types [...]

Author(s): Laurent Monney [1]; Catherine A. Sabatos [1]; Jason L. Gaglia [1]; Akemi Ryu [1]; Hanspeter Waldner [1]; Tatyana Chernova [2]; Stephen Manning [3]; Edward A. Greenfield [1, 2]; Anthony [...]

Author(s): Yu-Hwa Huang; Chen Zhu; Yasuyuki Kondo; Ana C. Anderson; Amit Gandhi; Andrew Russell; Stephanie K. Dougan; Britt-Sabina Petersen; Espen Melum; Thomas Pertel; Kiera L. Clayton; Monika Raab; Qiang Chen; [...]

The antigen-reactive cells, Th1 and Th2, are activated by high doses of oral antigens, an activation which then induces their deletion in Peyer's patches in mice which are transgenic for the ovalbumin-specific T-cell receptor genes. This deletion is due to apoptosis and depends on the antigen feeding frequency and dose. However, at low doses instead of deletion, antigen-specific cells, which form the transforming growth factor, interleukin-4 and Il-10 cytokines, are produced. Thus, the orally induced tolerance is created not only by suppression but also by deletion of the T cells.

Author(s): Li Yang [sup.1] , David E. Anderson [sup.1] , Clare Baecher-Allan [sup.1] , William D. Hastings [sup.1] , Estelle Bettelli [sup.1] , Mohamed Oukka [sup.1] , Vijay K. Kuchroo [...], Cytokines involved in T.sub.H17 cell differentiation T.sub.H17 cells (a subset of interleukin (IL)-17-producing T helper cells) are thought to contribute to the pathogenesis of a number of human autoimmune diseases. This study examines which cytokines are required for the production of IL-17A by memory and naive human CD4 T cells. The data demonstrate that transforming growth factor-[beta] (TGF-[beta]) is critical for the differentiation of T.sub.H17 cells from highly purified naive CD4.sup.+ T cells, but not necessary for induction of IL-17 from committed memory CD4.sup.+ T cells. The T.sub.H17 pathway is thought to contribute to the pathogenesis of a number of human autoimmune diseases. This study examines which cytokines are required for the production of IL-17A by memory and naive human CD4.sup.+ T cells. The recent discovery of CD4.sup.+ T cells characterized by secretion of interleukin (IL)-17 (T.sub.H17 cells) and the naturally occurring regulatory FOXP3.sup.+ CD4 T cell (nT.sub.reg) has had a major impact on our understanding of immune processes not readily explained by the T.sub.H1/T.sub.H2 paradigm. T.sub.H17 and nT.sub.reg cells have been implicated in the pathogenesis of human autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis.sup.1,2. Our recent data and the work of others demonstrated that transforming growth factor-[beta] (TGF-[beta]) and IL-6 are responsible for the differentiation of naive mouse T cells into T.sub.H17 cells, and it has been proposed that IL-23 may have a critical role in stabilization of the T.sub.H17 phenotype.sup.3,4,5. A second pathway has been discovered in which a combination of TGF-[beta] and IL-21 is capable of inducing differentiation of mouse T.sub.H17 cells in the absence of IL-6 (refs 6-8). However, TGF-[beta] and IL-6 are not capable of differentiating human T.sub.H17 cells.sup.2,9 and it has been suggested that TGF-[beta] may in fact suppress the generation of human T.sub.H17 cells.sup.10. Instead, it has been recently shown that the cytokines IL-1[beta], IL-6 and IL-23 are capable of driving IL-17 secretion in short-term CD4.sup.+ T cell lines isolated from human peripheral blood.sup.11, although the factors required for differentiation of naive human CD4 to T.sub.H17 cells are still unknown. Here we confirm that whereas IL-1[beta] and IL-6 induce IL-17A secretion from human central memory CD4.sup.+ T cells, TGF-[beta] and IL-21 uniquely promote the differentiation of human naive CD4.sup.+ T cells into T.sub.H17 cells accompanied by expression of the transcription factor RORC2. These data will allow the investigation of this new population of T.sub.H17 cells in human inflammatory disease.

TH17 cells (interleukin-17 (IL-17)-producing helper T cells) are highly proinflammatory cells that are critical for clearing extracellular pathogens and for inducing multiple autoimmune diseases. IL-23 has a critical role in stabilizing and reinforcing the TH17 phenotype by increasing expression of IL-23 receptor (IL-23R) and endowing TH17 cells with pathogenic effector functions. However, the precise molecular mechanism by which IL-23 sustains the TH17 response and induces pathogenic effector functions has not been elucidated. Here we used transcriptional profiling of developing TH17 cells to construct a model of their signalling network and nominate major nodes that regulate TH17 development. We identified serum glucocorticoid kinase 1 (SGK1), a serine/threonine kinase, as an essential node downstream of IL-23 signalling. SGK1 is critical for regulating IL-23R expression and stabilizing the TH17 cell phenotype by deactivation of mouse Foxo1, a direct repressor of IL-23R expression. SGK1 has been shown to govern Na+ transport and salt (NaCl) homeostasis in other cells. We show here that a modest increase in salt concentration induces SGK1 expression, promotes IL-23R expression and enhances TH17 cell differentiation in vitro and in vivo, accelerating the development of autoimmunity. Loss of SGK1 abrogated Na+-mediated TH17 differentiation in an IL-23-dependent manner. These data demonstrate that SGK1 has a critical role in the induction of pathogenic TH17 cells and provide a molecular insight into a mechanism by which an environmental factor such as a high salt diet triggers TH17 development and promotes tissue inflammation. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-17-producing T helper cells (TH17) are a recently identified CD4+ T cell subset distinct from T helper type 1 (TH1) and T helper type 2 (TH2) cells. TH17 cells can drive antigen-specific autoimmune diseases and are considered the main population of pathogenic T cells driving experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. The factors that are needed for the generation of TH17 cells have been well characterized. However, where and how the immune system controls TH17 cells in vivo remains unclear. Here, by using a model of tolerance induced by CD3-specific antibody, a model of sepsis and influenza A viral infection (H1N1), we show that pro-inflammatory TH17 cells can be redirected to and controlled in the small intestine. TH17-specific IL-17A secretion induced expression of the chemokine CCL20 in the small intestine, facilitating the migration of these cells specifically to the small intestine via the CCR6/CCL20 axis. Moreover, we found that TH17 cells are controlled by two different mechanisms in the small intestine: first, they are eliminated via the intestinal lumen; second, pro-inflammatory TH17 cells simultaneously acquire a regulatory phenotype with in vitro and in vivo immune-suppressive properties (rTH17). These results identify mechanisms limiting TH17 cell pathogenicity and implicate the gastrointestinal tract as a site for control of TH17 cells. [ABSTRACT FROM AUTHOR]

T helper (TH) cells constitute an important arm of the adaptive immune system because they coordinate defence against specific pathogens, and their unique cytokines and effector functions mediate different types of tissue inflammation. The recently discovered TH17 cells, the third subset of effector T helper cells, have been the subject of intense research aimed at understanding their role in immunity and disease. Here we review emerging data suggesting that TH17 cells have an important role in host defence against specific pathogens and are potent inducers of autoimmunity and tissue inflammation. In addition, the differentiation factors responsible for their generation have revealed an interesting reciprocal relationship with regulatory T (Treg) cells, which prevent tissue inflammation and mediate self-tolerance. [ABSTRACT FROM AUTHOR]

On activation, naive T cells differentiate into effector T-cell subsets with specific cytokine phenotypes and specialized effector functions. Recently a subset of T cells, distinct from T helper (TH)1 and TH2 cells, producing interleukin (IL)-17 (TH17) was defined and seems to have a crucial role in mediating autoimmunity and inducing tissue inflammation. We and others have shown that transforming growth factor (TGF)-β and IL-6 together induce the differentiation of TH17 cells, in which IL-6 has a pivotal function in dictating whether T cells differentiate into Foxp3+ regulatory T cells (Treg cells) or TH17 cells. Whereas TGF-β induces Foxp3 and generates Treg cells, IL-6 inhibits the generation of Treg cells and induces the production of IL-17, suggesting a reciprocal developmental pathway for TH17 and Treg cells. Here we show that IL-6-deficient (Il6-/-) mice do not develop a TH17 response and their peripheral repertoire is dominated by Foxp3+ Treg cells. However, deletion of Treg cells leads to the reappearance of TH17 cells in Il6-/- mice, suggesting an additional pathway by which TH17 cells might be generated in vivo. We show that an IL-2 cytokine family member, IL-21, cooperates with TGF-β to induce TH17 cells in naive Il6-/- T cells and that IL-21-receptor-deficient T cells are defective in generating a TH17 response. [ABSTRACT FROM AUTHOR]

On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (TH) cells are traditionally thought to differentiate into TH1 and TH2 cell subsets. TH1 cells are necessary to clear intracellular pathogens and TH2 cells are important for clearing extracellular organisms. Recently, a subset of interleukin (IL)-17-producing T (TH17) cells distinct from TH1 or TH2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury. In contrast, CD4+CD25+Foxp3+ regulatory T (Treg) cells inhibit autoimmunity and protect against tissue injury. Transforming growth factor-β (TGF-β) is a critical differentiation factor for the generation of Treg cells. Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation, completely inhibits the generation of Foxp3+ Treg cells induced by TGF-β. We also demonstrate that IL-23 is not the differentiation factor for the generation of TH17 cells. Instead, IL-6 and TGF-β together induce the differentiation of pathogenic TH17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (TH17) T cells that induce autoimmunity and regulatory (Foxp3+) T cells that inhibit autoimmune tissue injury. [ABSTRACT FROM AUTHOR]

The recent discovery of CD4+ T cells characterized by secretion of interleukin (IL)-17 (TH17 cells) and the naturally occurring regulatory FOXP3+ CD4 T cell (nTreg) has had a major impact on our understanding of immune processes not readily explained by the TH1/TH2 paradigm. TH17 and nTreg cells have been implicated in the pathogenesis of human autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis. Our recent data and the work of others demonstrated that transforming growth factor-β (TGF-β) and IL-6 are responsible for the differentiation of naive mouse T cells into TH17 cells, and it has been proposed that IL-23 may have a critical role in stabilization of the TH17 phenotype. A second pathway has been discovered in which a combination of TGF-β and IL-21 is capable of inducing differentiation of mouse TH17 cells in the absence of IL-6 (refs 6–8). However, TGF-β and IL-6 are not capable of differentiating human TH17 cells and it has been suggested that TGF-β may in fact suppress the generation of human TH17 cells. Instead, it has been recently shown that the cytokines IL-1β, IL-6 and IL-23 are capable of driving IL-17 secretion in short-term CD4+ T cell lines isolated from human peripheral blood, although the factors required for differentiation of naive human CD4 to TH17 cells are still unknown. Here we confirm that whereas IL-1β and IL-6 induce IL-17A secretion from human central memory CD4+ T cells, TGF-β and IL-21 uniquely promote the differentiation of human naive CD4+ T cells into TH17 cells accompanied by expression of the transcription factor RORC2. These data will allow the investigation of this new population of TH17 cells in human inflammatory disease. [ABSTRACT FROM AUTHOR]