Invariant natural killer T (iNKT) cells are a subset of innate-like lymphocytes that recognize glycolipid antigens bound by the major histocompatibility complex (MHC)-class-I-related protein CD1d. iNKT cells are activated early during a variety of infections and inflamma-tory diseases and contribute to the subsequent development of adaptive immune responses. Consequently, iNKT cells play a critical role in the development and resolution of inflammatory diseases and represent attractive targets for the development of immunotherapies. Recent studies have provided important insight into the mechanisms by which iNKT cells become activated in response to diverse inflammatory stimuli. These new findings should be instrumental to promote the immunomodulatory properties of iNKT cells for treatment of inflammatory diseases.
invariant natural killer T cells; CD1d; glycolipids; inflammation; immunotherapy
Endoplasmic reticulum (ER)-associated aminopeptidase (ERAP)1 has been implicated in the final proteolytic processing of peptides presented by major histocompatibility complex (MHC) class I molecules. To evaluate the in vivo role of ERAP1, we have generated ERAP1-deficient mice. Cell surface expression of the class Ia molecules H-2Kb and H-2Db and of the class Ib molecule Qa-2 was significantly reduced in these animals. Although cells from mutant animals exhibited reduced capacity to present several self- and foreign antigens to Kb-, Db-, or Qa-1b–restricted CD8+ cytotoxic T cells, presentation of some antigens was unaffected or significantly enhanced. Consistent with these findings, mice generated defective CD8+ T cell responses against class I–presented antigens. These findings reveal an important in vivo role of ER-associated peptidase activity in tailoring peptides for presentation by MHC class Ia and class Ib molecules.
Obesity is associated with a low-grade, chronic inflammation that promotes the development of a variety of diseases, most notably type 2 diabetes. A number of cell types of the innate and adaptive immune systems have been implicated in this process. Recent studies have focused on the role of natural killer T (NKT) cells, a subset of T lymphocytes that react with lipids, in the development of obesity-associated diseases. These studies have shown that invariant NKT (iNKT) cells, a population of NKT cells expressing a semi-invariant T cell receptor, become rapidly activated in response to lipid excess, and that these cells influence the capacity of other leukocytes to produce cytokines during the progression of obesity. The role of NKT cells in obesity-associated inflammation and insulin resistance has been investigated using NKT cell-deficient animals, adoptive transfer of NKT cells and an iNKT cell agonist. While divergent results have been obtained, it is now clear that NKT cells can modulate the inflammatory milieu in obesity, suggesting that these cells could be targeted for therapeutic intervention in obesity-associated diseases.
CD1d; diabetes; immunotherapy; inflammation; insulin resistance; lipid; metabolic disease; natural killer T cells; obesity
Patients suffering from ulcerative colitis (UC) exhibit chronic colonic inflammation caused by a dysregulated mucosal immune response and epithelial barrier disruption. Th2 cytokines, including IL-13, have been implicated in the pathogenesis of UC. IL-13 induces phosphorylation of STAT6, and we have previously demonstrated increased epithelial phosphorylated (p)STAT6 in children with UC. Here, we investigated the role of STAT6 in oxazolone colitis, a murine model of UC, by inducing colitis in STAT6-deficient (STAT6−/−) and wild type (WT) mice. We observed increased epithelial cell, T cell, macrophage, and NKT cell STAT6 phosphorylation, and increased pSTAT6+ IL-13-producing NKT cells, in colitic WT mice. Colitis was attenuated in STAT6−/− mice with improvements in weight, colon length, and histopathology. There was decreased induction of the pore-forming tight junction protein claudin-2 in STAT6−/− mice. Similarly, shRNA STAT6 knockdown reduced claudin-2 induction and transepithelial resistance decrease in IL-13-treated human T84 cells. Tissue expression of IL-13, IFN-γ, IL-17, and IL-10 mRNA was similarly induced in WT and STAT6−/− colitic mice; however, we observed increased mRNA expression for the Th2-inducing cytokines IL-33 and thymic stromal lymphopoietin (TSLP) in WT mice with colitis, which was abrogated in STAT6−/− mice. Mesenteric lymph node (MLN) cells from STAT6−/− mice with colitis exhibited reduced secretion of IL-4, IL-5, IL-13, and IFN-γ. IL-33 augmented MLN cell secretion of IL-5, IL-13, IL-6, and IFN-γ. These data implicate STAT6 in the pathogenesis of colitis in vivo with important roles in altering epithelial barrier function and regulating Th2-inducing cytokine production.
Mycobacterium tuberculosis, the causative agent of tuberculosis, resides
and replicates within susceptible hosts by inhibiting host antimicrobial mechanisms.
Prostaglandin E2 (PGE2), produced by M.
tuberculosis–infected macrophages, exerts a variety of immunomodulatory
functions via 4 receptors (EP1–EP4), each mediating distinct PGE2
functions. Here, we show that M. tuberculosis infection selectively
upregulates EP2 messenger RNA expression in CD4+ T cells.
We found that EP2 deficiency in mice increases susceptibility to M.
tuberculosis infection, which correlated with reduced antigen-specific T-cell
responses and increased levels of
CD4+CD25+Foxp3+ T-regulatory cells.
These findings have revealed an important role for EP2 in host immune defense against
tuberculosis. As a G protein-coupled receptor, EP2 could serve as a target for
immunotherapy of tuberculosis.
IL-4 contributes to immunopathology induced in mice by primary respiratory syncytial virus (RSV) infection. However, the cellular source of IL-4 in RSV infection is unknown. We identified CD3−CD49b+ cells as the predominant source of IL-4 in the lungs of RSV-infected BALB/c mice. We ruled out T cells, NK cells, NKT cells, mast cells, and eosinophils as IL-4 expressors in RSV infection by flow cytometry. Using IL4 GFP reporter mice (4get) mice, we identified the IL-4-expressing cells in RSV infection as basophils (CD3−CD49b+FcεRI+c-kit−). Because STAT1−/− mice have an enhanced Th2-type response to RSV infection, we also sought to determine the cellular source and role of IL-4 in RSV-infected STAT1−/− mice. RSV infection resulted in significantly more IL-4-expressing CD3−CD49b+ cells in the lungs of STAT1−/− mice than in BALB/c mice. CD49b+IL-4+ cells sorted from the lungs of RSV-infected STAT1−/− mice and stained with Wright-Giemsa had basophil characteristics. As in wild-type BALB/c mice, IL-4 contributed to lung histopathology in RSV-infected STAT1−/− mice. Depletion of basophils in RSV-infected STAT1−/− mice reduced lung IL-4 expression. Thus, we show for the first time that a respiratory virus (RSV) induced basophil accumulation in vivo. Basophils were the primary source of IL-4 in the lung in RSV infection, and STAT1 was a negative regulator of virus-induced basophil IL-4 expression.
basophils; cytokines; viral; lung
In vitro CD4+ T cell differentiation systems have made important contributions to understanding the mechanisms underlying the differentiation of naive CD4+ T cells into effector cells with distinct biological functions. Mature CD4+ T cells expressing CD8αα homodimers are primarily found in the intestinal mucosa of men and mice, and to a lesser extent in other tissues such as peripheral blood. Although CD4+CD8α+ T cells are easily identified, very little is known about their development and immunological functions. It has been reported, however, that CD4+CD8α+ T cells possess regulatory properties. In this report, we present a novel in vitro differentiation system where CD4+ T cells are stimulated to become CD4+CD8α+ T cells in the presence of TGF-β, IL-7 and IFN-γ, resulting in cells with very similar features as CD4+CD8α+ intraepithelial lymphocytes. This novel in vitro differentiation culture should provide a powerful and tractable tool for dissecting the differentiation and biological functions of CD4+CD8α+ T cells.
Natural killer T (NKT) cells are a subset of T lymphocytes that share surface markers and functional characteristics with both conventional T lymphocytes and natural killer cells. Most NKT cells express a semiinvariant T cell receptor that reacts with glycolipid antigens presented by the major histocompatibility complex class I-related protein CD1d on the surface of antigen-presenting cells. NKT cells become activated during a variety of infections and inflammatory conditions, rapidly producing large amounts of immunomodulatory cytokines. NKT cells can influence the activation state and functional properties of multiple other cell types in the immune system and, thus, modulate immune responses against infectious agents, autoantigens, tumors, tissue grafts and allergens. One attractive aspect of NKT cells is that their immunomodulatory activities can be readily harnessed with cognate glycolipid antigens, such as the marine sponge-derived glycosphingolipid alpha-galactosylceramide. These properties of NKT cells are being exploited for therapeutic intervention to prevent or treat cancer, infections, and autoimmune and inflammatory diseases.
Natural killer T cells; Innate Immunity; Glycolipid Antigens; CD1d; Immunotherapy; Immunomodulation; Vaccine Adjuvants; Review
Natural killer (NK) cells can be swiftly mobilized by danger signals and are among the earliest arrivals at target organs of disease. However, the role of NK cells in mounting inflammatory responses is often complex and sometimes paradoxical. Here, we examine the divergent phenotypic and functional features of NK cells, as deduced largely from experimental mouse models of pathophysiological responses in the liver, mucosal tissues, uterus, pancreas, joints and brain. Moreover, we discuss how organ-specific factors, the local microenvironment and unique cellular interactions may influence the organ-specific properties of NK cells.
Invariant natural killer T (iNKT) cells are innate lymphocytes with unique specificity for glycolipid antigens and remarkable immunomodulatory properties. The role of costimulatory interactions in iNKT cell responses has recently come under scrutiny. Although iNKT cells and their prototype glycolipid agonist α-galactosylceramide (α-GalCer) have shown promise in several clinical trials conducted in patients with cancer or viral diseases, current iNKT cell-based therapies are far from effective. The concomitant targeting of T cell receptors (TCRs) and costimulatory molecules on iNKT cells represents an exciting new opportunity to optimize such therapeutic approaches. Here, we review recent advances in our understanding of iNKT cell costimulation and discuss potential treatment modalities based on the responsiveness of iNKT cells to disease-tailored glycolipids and select costimulatory ligands.
Cells of the innate immune system interact with pathogens via conserved pattern-recognition receptors, whereas cells of the adaptive immune system recognize pathogens through diverse, antigen-specific receptors that are generated by somatic DNA rearrangement. Invariant natural killer T (iNKT) cells are a subset of lymphocytes that bridge the innate and adaptive immune systems. Although iNKT cells express T cell receptors that are generated by somatic DNA rearrangement, these receptors are semi-invariant and interact with a limited set of lipid and glycolipid antigens, thus resembling the pattern-recognition receptors of the innate immune system. Functionally, iNKT cells most closely resemble cells of the innate immune system, as they rapidly elicit their effector functions following activation, and fail to develop immunological memory. iNKT cells can become activated in response to a variety of stimuli and participate in the regulation of various immune responses. Activated iNKT cells produce several cytokines with the capacity to jump-start and modulate an adaptive immune response. A variety of glycolipid antigens that can differentially elicit distinct effector functions in iNKT cells have been identified. These reagents have been employed to test the hypothesis that iNKT cells can be harnessed for therapeutic purposes in human diseases. Here, we review the innate-like properties and functions of iNKT cells and discuss their interactions with other cell types of the immune system.
CD1d; Glycolipids; Immunomodulation; Innate immunity; Invariant natural killer T cells
Human autoimmune diseases are often characterized by a relative deficiency in CD4+CD25+ regulatory T cells (Treg). We therefore hypothesized that expansion of Treg can ameliorate autoimmune pathology. We tested this hypothesis in an experimental model for autoimmune myasthenia gravis (MG), a B-cell-mediated disease characterized by auto-Ab directed against the acetylcholine receptorwithin neuromuscular junctions. We showed that injection of immune complexes composed of the cytokine IL-2 and anti-IL-2 mAb (JES6-1A12) induced an effective and sustained expansion of Treg,via peripheral proliferation of CD4+CD25+Foxp3+ cells and peripheral conversion of CD4+CD25−Foxp3− cells. The expanded Treg potently suppressed autoreactive T- and B-cell responses to acetylcholine receptor and attenuated themuscular weakness that is characteristic ofMG. Thus, IL-2/anti-IL-2 mAb complexes can expand functional Treg in vivo, providing a potential clinical application of this modality for treatment of MG and other autoimmune disorders.
Autoimmunity; IL-2/IL-2 mAb complexes; Myasthenia Gravis; Self-tolerance; Treg
Cytoplasmic Ags derived from viruses, cytosolic bacteria, tumours and allografts are presented to T cells by MHC class I or class II molecules. In the case of class II-restricted Ags, professional Ag-presenting cells acquire them during uptake of dead, class II-negative cells and present them via a process called indirect presentation. It is generally assumed that the cytosolic Ag-processing machinery—which supplies peptides for presentation by class I molecules—plays very little role in indirect presentation of class II-restricted, cytoplasmic Ags. Remarkably, upon testing this assumption, we found that proteasomes, TAP and ERAAP, but not tapasin, partially destroyed or removed cytoplasmic, class II-restricted Ags such that their inhibition or deficiency led to dramatically increased TH cell responses to allograft (HY) and microbial (Listeria monocytogenes) Ags, both of which are indirectly presented. This effect was neither due to enhanced ER-associated degradation nor competition for Ag between class I and class II molecules. From these findings a novel model emerges in which the cytosolic Ag-processing machinery regulates the quantity of cytoplasmic peptides available for presentation by class II molecules, and hence modulates TH cell responses.
Semi-invariant natural killer T (NKT) cells are thymus-derived innate lymphocytes that modulate microbial and tumour immunity as well as autoimmune diseases. These immunoregulatory properties of NKT cells are acquired during their development. Much has been learnt regarding the molecular and cellular cues that promote NKT cell development, yet how these cells are maintained in the thymus and the periphery and how they acquire functional competence are incompletely understood. We found that IL-15 induced several Bcl-2 family survival factors in thymic and splenic NKT cells in vitro. Yet, IL15-mediated thymic and peripheral NKT cell survival critically depended on Bcl-xL expression. Additionally, IL-15 regulated thymic developmental stage 2 (ST2) to ST3 lineage progression and terminal NKT cell differentiation. Global gene expression analyses and validation revealed that IL-15 regulated Tbx21 (T-bet) expression in thymic NKT cells. The loss of IL15 also resulted in poor expression of key effector molecules such as IFN-γ, granzyme A and C as well as several NK cell receptors in NKT cells. Taken together, our findings reveal a critical role for IL-15 in NKT cell survival, which is mediated by Bcl-xL, and effector differentiation, which is consistent with a role of T-bet in regulating terminal maturation.
Background: Modulation of host miRNAs coincides with increased pathogenicity in various infectious diseases.
Results: miR-99b is up-regulated in M. tuberculosis-infected dendritic cells, which inhibits production of proinflammatory cytokines.
Conclusion: Our findings unfold a novel immune evasion strategy of M. tuberculosis by modulating miRNAs.
Significance: Our study opens up the possibility to design vaccines and immunotherapies for tuberculosis by targeting specific miRNAs.
Mycobacterium tuberculosis resides and replicates within host phagocytes by modulating host microbicidal responses. In addition, it suppresses the production of host protective cytokines to prevent activation of and antigen presentation by M. tuberculosis-infected cells, causing dysregulation of host protective adaptive immune responses. Many cytokines are regulated by microRNAs (miRNAs), a newly discovered class of small noncoding RNAs, which have been implicated in modulating host immune responses in many bacterial and viral diseases. Here, we show that miRNA-99b (miR-99b), an orphan miRNA, plays a key role in the pathogenesis of M. tuberculosis infection. We found that miR-99b expression was highly up-regulated in M. tuberculosis strain H37Rv-infected dendritic cells (DCs) and macrophages. Blockade of miR-99b expression by antagomirs resulted in significantly reduced bacterial growth in DCs. Interestingly, knockdown of miR-99b in DCs significantly up-regulated proinflammatory cytokines such as IL-6, IL-12, and IL-1β. Furthermore, mRNA and membrane-bound protein data indicated that inhibition of miR-99b augments TNF-α and TNFRSF-4 production. Thus, miR-99b targets TNF-α and TNFRSF-4 receptor genes. Treatment of anti-miR-99b-transfected DCs with anti-TNF-α antibody resulted in increased bacterial burden. Thus, our findings unveil a novel host evasion mechanism adopted by M. tuberculosis via miR-99b, which may open up new avenues for designing miRNA-based vaccines and therapies.
Innate immunity; MicroRNA; Mycobacterium tuberculosis; T cell; Tumor necrosis factor (TNF); DCs
Islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP), now known as G6PC2, is a major target of autoreactive T cells implicated in the pathogenesis of type 1 diabetes in both mice and humans. This study aimed to determine whether suppression of G6p2 gene expression might therefore prevent or delay disease progression.
RESEARCH DESIGN AND METHODS
G6pc2−/− mice were generated on the NOD/ShiLtJ genetic background, and glycemia was monitored weekly up to 35 weeks of age to determine the onset and incidence of diabetes. The antigen specificity of CD8+ T cells infiltrating islets from NOD/ShiLtJ G6pc2+/+ and G6pc2−/− mice at 12 weeks was determined in parallel.
The absence of G6pc2 did not affect the time of onset, incidence, or sex bias of type 1 diabetes in NOD/ShiLtJ mice. Insulitis was prominent in both groups, but whereas NOD/ShiLtJ G6pc2+/+ islets contained CD8+ T cells reactive to the G6pc2 NRP peptide, G6pc2 NRP-reactive T cells were absent in NOD/ShiLtJ G6pc2−/− islets.
These results demonstrate that G6pc2 is an important driver for the selection and expansion of islet-reactive CD8+ T cells infiltrating NOD/ShiLtJ islets. However, autoreactivity to G6pc2 is not essential for the emergence of autoimmune diabetes. The results remain consistent with previous studies indicating that insulin may be the primary autoimmune target, at least in NOD/ShiLtJ mice.
The intestinal epithelium is comprised of a monolayer of intestinal epithelial cells (IEC) which provide, among other functions, a physical barrier between the high antigen content of the intestinal lumen and the sterile environment beyond the epithelium. IEC express a non-classical MHC class I molecule known as the thymus leukemia (TL) antigen. TL is known to interact with CD8αα-expressing cells, which are abundant in the intestinal intraepithelial lymphocyte compartment. In this report we provide evidence indicating that expression of TL by IEC modulates the cytokine profile of CD4+ T cells favoring IL-17 production. We show in an adoptive transfer model of colitis that donor-derived cells become more pathogenic when TL is expressed on IEC in recipient animals. Moreover, TL+IEC promote development of IL-17-mediated responses capable of protecting mice from Citrobacter rodentium infection. We also show that modulation of IL-17-mediated responses by TL+IEC is controlled by the expression of CD8α on CD4+ T cells. Overall, our results provide evidence for an important interaction between IEC and CD4+ T cells via TL, which modulates mucosal immune responses.
Mycobacterium tuberculosis survives within the host by modulating host immune responses.
Results: RD-1/ESAT-6 from M. tuberculosis induces IL-1β in dendritic cells to direct Th2 differentiation, which facilitates disease progression by inhibiting host protective Th1 responses.
Conclusion: Cytokines produced by M. tuberculosis-infected cells play a role in promoting Th2 responses to subvert host immunity.
Significance: These findings contribute to understanding the immune evasion mechanisms of M. tuberculosis.
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), resides and replicates within phagocytes and persists in susceptible hosts by modulating protective innate immune responses. Furthermore, M. tuberculosis promotes T helper 2 (Th2) immune responses by altering the balance of T cell polarizing cytokines in infected cells. However, cytokines that regulate Th2 cell differentiation during TB infection remain unknown. Here we show that IL-1β, produced by phagocytes infected by virulent M. tuberculosis strain H37Rv, directs Th2 cell differentiation. In sharp contrast, the vaccine strain bacille Calmette-Guérin as well as RD-1 and ESAT-6 mutants of H37Rv failed to induce IL-1β and promote Th2 cell differentiation. Furthermore, ESAT-6 induced IL-1β production in dendritic cells (DCs), and CD4+ T cells co-cultured with infected DCs differentiated into Th2 cells. Taken together, our findings indicate that IL-1β induced by RD-1/ESAT-6 plays an important role in the differentiation of Th2 cells, which in turn facilitates progression of TB by inhibiting host protective Th1 responses.
Cytokine; Dendritic Cells; Interleukin; Mycobacterium tuberculosis; T Cell
Background: The mechanism by which BALB/c mice exhibit a propensity to induce T helper 2 (Th2) responses and allergic diseases is unknown.
Results: Prostaglandin endoperoxide E2 (PGE2) prevents activation-induced cell death in Th2 cells of BALB/c mice via the E-prostanoid 2 (EP2) receptor and is dependent on granzyme B.
Conclusion: Signaling of PGE2 through EP2 promotes Th2 immune responses.
Significance: EP2 can be targeted as a therapeutic modality for Th2-mediated diseases.
T helper 2 (Th2) cells play a central role in the progression of many diseases such as allergic airway inflammation, autoimmune diseases, and infections caused by intracellular pathogens. Consequently, animals such as BALB/c mice, which exhibit a propensity for generating Th2 responses, are susceptible to allergic airway inflammation, type-II autoimmune diseases, and various infections induced by intracellular pathogens, namely, Leishmania. In contrast, C3H/OuJ mice have a tendency for generating T helper 1 (Th1) responses and show resistance to these diseases. Here, we show that prostaglandin endoperoxide E2 selectively inhibits activation-induced cell death of Th2 cells by signaling through its receptor E-prostanoid receptor 2 (EP2). Consequently, Th2 cells derived from BALB/c mice expressed very high levels of EP2. On the other hand, Th2 cells derived from C3H/OuJ mice expressed very low levels of EP2, which failed to support the survival of Th2 cells. Furthermore, we found that this effect of EP2 on Th2 cells from BALB/c mice was executed by a granzyme B-mediated mechanism. EP2 belongs to a group of G-protein-coupled receptors that are amenable to therapeutic targeting. Our findings therefore identify EP2 as a promising target for small molecule-directed immunomodulation.
Cell Death; Cytokine; Immunology; Prostaglandins; T Cell; T Cell Biology; Activation-induced Cell Death; E Prostanoid Receptor EP2
The presence of immune memory at pathogen entry sites is a prerequisite for protection. Nevertheless, the mechanisms that warrant immunity at peripheral interfaces are not understood. Here we show that the non-classical MHC class I molecule, the thymus leukemia antigen (TL), induced on dendritic cells interacting with CD8αα on activated CD8αβ+T cells, mediated affinity-based selection of memory precursor cells. Furthermore, constitutive expression of TL on epithelial cells led to continued selection of mature CD8αβ memory T cells. The TL-CD8αα-driven memory process was essential for the generation of memory CD8αβ T cells in the intestine and accumulation of highly antigen sensitive CD8αβ memory T cells that form the first line of defense at the largest entry port for pathogens.
The role of natural killer (NK) cells in regulating multiple sclerosis (MS) is not well understood. Additional studies with NK cells might provide insight into the mechanism of action of MS therapies such as daclizumab, an antibody against the IL-2R α-chain, which induces expansion of CD56bright NK cells.
In a relapsing-remitting form of the experimental autoimmune encephalomyelitis (EAE) model of MS induced in SJL mice, we expanded NK cells with IL-2 coupled with an anti-IL-2 mAb and evaluated the effects of these NK cells on EAE. Further, we investigated the effect of the human version of IL-2/IL-2 mAb on NK cells from MS patients and its effect on CNS inflammation and pathology in a human-mouse chimera model and assessed the underlying mechanisms.
IL-2/IL-2 mAb dramatically expands NK cells both in the peripheral lymphoid organs and in the central nervous system (CNS), and attenuates CNS inflammation and neurological deficits. Disease protection is conferred by CNS-resident NK cells. Importantly, the human version of IL-2/IL-2 mAb restored the defective CD56+ NK cells from MS patients in a human-mouse chimera model. Both the CD56bright and CD56dim subpopulations were required to attenuate disease in this model.
These findings unveil the immunotherapeutic potential of NK cells, which can act as critical suppressor cells in target organs of autoimmunity. These results also have implications to better understand the mechanism of action of daclizumab in MS.
Glatiramer acetate (GA, copolymer-1, Copaxone®) is a Food and Drug Administration-approved drug for the treatment of relapsing-remitting multiple sclerosis (MS). However, its mechanism of action remains ill-defined. The available evidence indicates that GA induces antigen-presenting cells with anti-inflammatory properties and promotes the generation of immunoregulatory T cells that suppress pathogenic T cells. A new study by Kala et al. (Exp. Neurol. 2010. 221, 136–145) now shows that B lymphocytes, which are best known for their antibody-secreting properties, contribute to the beneficial effects of GA against experimental autoimmune encephalomyelitis (EAE), the animal model of MS. This commentary discusses these new findings in the context of the pathogenesis of MS and EAE, the emerging immunoregulatory role of B cells in autoimmunity, and the relevance of B cells as targets for immunotherapy in MS.
Antigen-presenting cells; Experimental autoimmune encephalomyelitis; Glatiramer acetate/copolymer 1/Copaxone®; Immunomodulation; Multiple sclerosis; Pathogenic T cells; Regulatory B cells; Regulatory T cells; Treatment
In vitro TGF-β differentiates Th17 and Tc17 cells, but TGF-βRIIDN mice display multiorgan autoimmune disorders.
Results: CD4+T cells from TGF-βRIIDN mice are resistant to Th17 cell differentiation, whereas CD8+T cells acquire IL-17-producing phenotype, and IL-17 neutralization or depletion inhibited inflammation in TGF-βRIIDN mice.
Conclusion: Tc17 cell differentiations in vivo are distinct from Tc17 cell differentiations in vitro.
Significance: The Tc17 cell differentiation program is unique to Th17.
TGF-β is a pleiotropic cytokine that predominantly exerts inhibitory functions in the immune system. Unexpectedly, the in vitro differentiation of both Th17 and Tc17 cells requires TGF-β. However, animals that are impaired in TGF-β signaling (TGF-βRIIDN mice) display multiorgan autoimmune disorders. Here we show that CD4+ T cells from TGF-βRIIDN mice are resistant to Th17 cell differentiation and, paradoxically, that CD8+ T cells from these animals spontaneously acquire an IL-17-producing phenotype. Neutralization of IL-17 or depletion of CD8+ T cells dramatically inhibited inflammation in TGF-βRIIDN mice. Therefore, the absence of TGF-β triggers spontaneous differentiation of IL-17-producing CD8+ T cells, suggesting that the in vivo and in vitro conditions that promote the differentiation of IL-17-producing CD8+ T cells are distinct.
Cytokine; Inflammatory Bowel Disease; Interleukin; T cell; Transforming Growth Factor Beta (TGFbeta); CD4 T Cell; CD8 T Cell; IL-17; IL-6
The intestinal mucosa represents a large surface area that is in contact with an immense antigenic load. The immune system associated with the intestinal mucosa needs to distinguish between innocuous food antigens, commensal microorganisms, and pathogenic microorganisms, without triggering an exaggerated immune response that may lead to excessive inflammation and/or development of inflammatory bowel disease. The thymus leukemia (TL) antigen and CD8αα are interacting surface molecules that are expressed at the frontline of the mucosal immune system: TL is expressed in intestinal epithelial cells (IEC) whereas CD8αα is expressed in lymphocytes, known as intraepithelial lymphocytes, that reside in between the IEC. In this review we discuss the significance of the interaction between TL and CD8αα in mucosal immunity during health and disease.
Thymus leukemia antigen; CD8αα; mucosal immunology; immune regulation
Despite its relatively poor efficacy, Bacillus Calmette-Guérin (BCG) has been used as a tuberculosis (TB) vaccine since its development in 1921. BCG induces robust T helper 1 (Th1) immune responses but, for many individuals, this is not sufficient for host resistance against Mycobacterium tuberculosis (M. tb) infection. Here we provide evidence that early secreted antigenic target protein 6 (ESAT-6), expressed by the virulent M. tb strain H37Rv but not by BCG, promotes vaccine-enhancing Th17 cell responses. These activities of ESAT-6 were dependent on TLR-2/MyD88 signalling and involved IL-6 and TGF-β production by dendritic cells. Thus, animals that were previously infected with H37Rv or recombinant BCG containing the RD1 region (BCG::RD1) exhibited improved protection upon re-challenge with virulent H37Rv compared with mice previously infected with BCG or RD1-deficient H37Rv (H37RvΔRD1). However, TLR-2 knockout (TLR-2-/-) animals neither showed Th17 responses nor exhibited improved protection in response to immunization with H37Rv. Furthermore, H37Rv and BCG::RD1 infection had little effect on the expression of the anti-inflammatory microRNA-146a (miR146a) in dendritic cells (DCs), whereas BCG and H37RvΔRD1 profoundly induced its expression in DCs. Consistent with these findings, ESAT-6 had no effect on miR146a expression in uninfected DCs, but dramatically inhibited its upregulation in BCG-infected or LPS-treated DCs. Collectively, our findings indicate that, in addition to Th1 immunity induced by BCG, RD1/ESAT-6-induced Th17 immune responses are essential for optimal vaccine efficacy.
Tuberculosis is a global health problem, with one-third of the global population infected with tubercle bacteria. Numerous studies have shown that Th1 cell responses are indispensable for protective immunity against TB. However, while the vaccine strain BCG induces sufficient Th1 cell response, this response does not appear to be sufficient for immune protection in many individuals. Here, we provide evidence for the first time that Th17 cell responses in the lung play a critical role for enhanced protection against TB. Surprisingly, the virulent M. tb strain H37Rv induced Th17 cell responses in the lung. Consequently, antibiotic-treated animals that were previously infected with H37Rv, as compared with similarly treated BCG-infected mice, generated improved protective immune responses against infection with virulent M. tb. We also provide evidence that the ESAT-6 protein, which is absent in BCG but present in H37Rv, induces IL-6 and TGF-β in dendritic cells in a TLR-2 and MyD88-dependent manner, which generates an environment that is conducive for the differentiation of Th17 cells in the lung. Our findings indicate that, in addition to Th1 cells, Th17 cells play a critical role in conferring optimal protection against TB.