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1.  T cell-derived Protein S engages TAM signaling in Dendritic Cells to control the magnitude of the immune response 
Immunity  2013;39(1):160-170.
Dendritic cell (DC) activation is essential for the induction of immune defense against pathogens, yet needs to be tightly controlled to avoid chronic inflammation and exaggerated immune responses. Here, we identify a mechanism of immune homeostasis by which adaptive immunity, once triggered, tempers DC activation and prevents overreactive immune responses. T cells, once activated, produce Protein S (Pros1) that signals through the TAM receptor tyrosine kinases in DCs to limit the magnitude of DC activation. Genetic ablation of Pros1 in mouse T cells leads to increased expression of co-stimulatory molecules and cytokines in DCs, enhanced immune responses to T cell-dependent antigens, as well as increased colitis. Additionally, PROS1 is expressed in activated human T cells and its ability to regulate DC activation is conserved. Our results identify a heretofore unrecognized, homeostatic negative feedback mechanism at the interface of adaptive and innate immunity that maintains the physiological magnitude of the immune response.
PMCID: PMC4017237  PMID: 23850380
2.  Intestinal monocytes and macrophages are required for T cell polarization in response to Citrobacter rodentium 
The Journal of Experimental Medicine  2013;210(10):2025-2039.
Using a new mouse model, the specific deletion of monocytes and macrophages reveals that, although not required to initiate immunity to Citrobacter rodentium, they contribute to the adaptive response via IL-12 secretion to induced IFN-γ+ Th1 polarization.
Dendritic cells (DCs), monocytes, and macrophages are closely related phagocytes that share many phenotypic features and, in some cases, a common developmental origin. Although the requirement for DCs in initiating adaptive immune responses is well appreciated, the role of monocytes and macrophages remains largely undefined, in part because of the lack of genetic tools enabling their specific depletion. Here, we describe a two-gene approach that requires overlapping expression of LysM and Csf1r to define and deplete monocytes and macrophages. The role of monocytes and macrophages in immunity to pathogens was tested by their selective depletion during infection with Citrobacter rodentium. Although neither cell type was required to initiate immunity, monocytes and macrophages contributed to the adaptive immune response by secreting IL-12, which induced Th1 polarization and IFN-γ secretion. Thus, whereas DCs are indispensable for priming naive CD4+ T cells, monocytes and macrophages participate in intestinal immunity by producing mediators that direct T cell polarization.
PMCID: PMC3782042  PMID: 24043764
3.  Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract 
The Journal of Experimental Medicine  2013;210(9):1871-1888.
Lung DCs induce the expression of gut-homing molecules on T cells, resulting in their migration to the GI tract and protection against Salmonella infection after immunization
Developing efficacious vaccines against enteric diseases is a global challenge that requires a better understanding of cellular recruitment dynamics at the mucosal surfaces. The current paradigm of T cell homing to the gastrointestinal (GI) tract involves the induction of α4β7 and CCR9 by Peyer’s patch and mesenteric lymph node (MLN) dendritic cells (DCs) in a retinoic acid–dependent manner. This paradigm, however, cannot be reconciled with reports of GI T cell responses after intranasal (i.n.) delivery of antigens that do not directly target the GI lymphoid tissue. To explore alternative pathways of cellular migration, we have investigated the ability of DCs from mucosal and nonmucosal tissues to recruit lymphocytes to the GI tract. Unexpectedly, we found that lung DCs, like CD103+ MLN DCs, up-regulate the gut-homing integrin α4β7 in vitro and in vivo, and induce T cell migration to the GI tract in vivo. Consistent with a role for this pathway in generating mucosal immune responses, lung DC targeting by i.n. immunization induced protective immunity against enteric challenge with a highly pathogenic strain of Salmonella. The present report demonstrates novel functional evidence of mucosal cross talk mediated by DCs, which has the potential to inform the design of novel vaccines against mucosal pathogens.
PMCID: PMC3754860  PMID: 23960190
4.  Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth 
Nature  2012;491(7423):254-258.
Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tumour suppressor and activation of β-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumour emerges and progresses1,2. Curiously, however, ‘inflammatory signature’ genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer3,4. Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates5, referred to as ‘tumour elicited inflammation’6. Although infiltrating CD4+ TH1 cells and CD8+ cytotoxic T cells constitute a positive prognostic sign in colorectal cancer7,8, myeloid cells and T-helper interleukin (IL)-17-producing (TH17) cells promote tumorigenesis5,6, and a ‘TH17 expression signature’ in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival9. Despite its pathogenic importance, the mechanisms responsible for the appearance of tumour-elicited inflammation are poorly understood. Many epithelial cancers develop proximally to microbial communities, which are physically separated from immune cells by an epithelial barrier10. We investigated mechanisms responsible for tumour-elicited inflammation in a mouse model of colorectal tumorigenesis, which, like human colorectal cancer, exhibits upregulation of IL-23 and IL-17. Here we show that IL-23 signalling promotes tumour growth and progression, and development of a tumoural IL-17 response. IL-23 is mainly produced by tumour-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumours but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. We propose that barrier deterioration induced by colorectal-cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumour-elicited inflammation, which in turn drives tumour growth.
PMCID: PMC3601659  PMID: 23034650
5.  Mutual expression of Runx3 and ThPOK regulates intestinal CD4+ T cell immunity 
Nature immunology  2013;14(3):271-280.
The gut mucosa hosts large numbers of activated lymphocytes, exposed to stimuli from diet, microbiota and pathogens. Although CD4+ T cells are crucial for defense, intestinal homeostasis precludes exaggerated response towards luminal contents, harmful or not. We investigated mechanisms used by CD4+ T cells to avoid excessive activation within the intestine. Using genetic tools to label and interfere with T cell development transcription factors we show that CD4+ T cells acquired CD8-lineage transcription factor Runx3 while losing CD4-lineage transcription factor ThPOK along with their TH17 differentiation and colitogenic potential, in a transforming growth factor-β (TGF-β) and retinoic-acid-dependent manner. These results show a remarkable plasticity in the CD4+ T cell lineage that allows chronic exposure to luminal antigens without pathological inflammation.
PMCID: PMC3804366  PMID: 23334789
6.  Transcriptional Reprogramming of Mature CD4+ T helper Cells generates distinct MHC class II-restricted Cytotoxic T Lymphocytes 
Nature immunology  2013;14(3):281-289.
TCRαβ thymocytes differentiate to either CD8αβ cytotoxic T lymphocytes or CD4+ T helper cells. This functional dichotomy is controlled by key transcription factors, including the T helper master regulator, ThPOK, which suppresses the cytolytic program in MHC class II-restricted CD4+ thymocytes. ThPOK continues to repress CD8-lineage genes in mature CD4+ T cells, even as they differentiate to T helper effector subsets. Here we show that the T helper-fate was not fixed and that mature antigen-stimulated CD4+ T cells could terminate Thpok expression and reactivate CD8-lineage genes. This unexpected plasticity resulted in the post-thymic termination of the T helper-program and the functional differentiation of distinct MHC class II-restricted CD4+ cytotoxic T lymphocytes.
PMCID: PMC3581083  PMID: 23334788
7.  Specialized role of migratory dendritic cells in peripheral tolerance induction 
Harnessing DCs for immunotherapies in vivo requires the elucidation of the physiological role of distinct DC populations. Migratory DCs traffic from peripheral tissues to draining lymph nodes charged with tissue self antigens. We hypothesized that these DC populations have a specialized role in the maintenance of peripheral tolerance, specifically, to generate suppressive Foxp3+ Tregs. To examine the differential capacity of migratory DCs versus blood-derived lymphoid-resident DCs for Treg generation in vivo, we targeted a self antigen, myelin oligodendrocyte glycoprotein, using antibodies against cell surface receptors differentially expressed in these DC populations. Using this approach together with mouse models that lack specific DC populations, we found that migratory DCs have a superior ability to generate Tregs in vivo, which in turn drastically improve the outcome of experimental autoimmune encephalomyelitis. These results provide a rationale for the development of novel therapies targeting migratory DCs for the treatment of autoimmune diseases.
PMCID: PMC3561796  PMID: 23298832
8.  The light and dark sides of intestinal intraepithelial lymphocytes 
Nature reviews. Immunology  2011;11(7):445-456.
The intraepithelial lymphocytes (IELs) that reside within the epithelium of the intestine form one of the main branches of the immune system. As IELs are located at this critical interface between the core of the body and the outside environment, they must balance protective immunity with an ability to safeguard the integrity of the epithelial barrier: failure to do so would compromise homeostasis of the organism. In this Review, we address how the unique development and functions of intestinal IELs allow them to achieve this balance.
PMCID: PMC3140792  PMID: 21681197
10.  Hepatic Stellate Cells Function as Regulatory Bystanders 
Regulatory T cells (Treg) contribute significantly to the tolerogenic nature of the liver. The mechanisms however underlying liver-associated Treg induction are still elusive. We recently identified the vitamin A (VitA) metabolite, retinoic acid (RA), as a key-controller, which promotes TGF-β–dependent Foxp3+ Treg induction but inhibits TGF-β driven Th17 differentiation. To investigate whether the RA producing hepatic stellate cells (HSC) are part of the liver tolerance mechanism, we investigated the ability of HSC to function as regulatory APC. Different from previous reports, we found that highly purified HSC did not express costimulatory molecules and only upregulated MHC class II after in vitro culture in the presence of exogenous IFN-γ. Consistent with an insufficient APC function, HSC failed to stimulate naïve OT-II TCR transgenic (OT-II) CD4+T cells and only moderately stimulated α-GalCer primed invariant NKT (iNKT) cells. In contrast, HSC functioned as regulatory bystanders and promoted enhanced Foxp3 induction by OT-II T cells primed by spleen dendritic cells (DC) whereas they greatly inhibited the Th17 differentiation. Furthermore, the regulatory bystander capacity of the HCS was completely dependent on their ability to produce RA. Our data thus suggest that HSC can function as regulatory bystanders and therefore by promoting Tregs and suppressing Th17 differentiation, they might represent key-players in the mechanism that drives liver induced tolerance.
PMCID: PMC3132534  PMID: 21460203
11.  Regulatory T Cells Accumulate in the Lung Allergic Inflammation and Efficiently Suppress T-Cell Proliferation but Not Th2 Cytokine Production 
Foxp3+CD25+CD4+ regulatory T cells are vital for peripheral tolerance and control of tissue inflammation. In this study, we characterized the phenotype and monitored the migration and activity of regulatory T cells present in the airways of allergic or tolerant mice after allergen challenge. To induce lung allergic inflammation, mice were sensitized twice with ovalbumin/aluminum hydroxide gel and challenged twice with intranasal ovalbumin. Tolerance was induced by oral administration of ovalbumin for 5 consecutive days prior to OVA sensitization and challenge. We detected regulatory T cells (Foxp3+CD25+CD4+ T cells) in the airways of allergic and tolerant mice; however, the number of regulatory T cells was more than 40-fold higher in allergic mice than in tolerant mice. Lung regulatory T cells expressed an effector/memory phenotype (CCR4highCD62LlowCD44highCD54highCD69+) that distinguished them from naive regulatory T cells (CCR4intCD62LhighCD44intCD54intCD69−). These regulatory T cells efficiently suppressed pulmonary T-cell proliferation but not Th2 cytokine production.
PMCID: PMC3227414  PMID: 22162718
12.  The Role of the Intestinal Context in the Generation of Tolerance and Inflammation 
The mucosal surface of the intestine alone forms the largest area exposed to exogenous antigens as well as the largest collection of lymphoid tissue in the body. The enormous amount of nonpathogenic and pathogenic bacteria and food-derived antigens that we are daily exposed sets an interesting challenge to the immune system: a protective immune activity must coexist with efficient regulatory mechanisms in order to maintain a health status of these organisms. This paper discusses how the immune system assimilates the perturbations from the environment without generating tissue damage.
PMCID: PMC3178197  PMID: 21949668
13.  The importance of being earnestly selfish 
Nature immunology  2009;10(10):1047-1049.
Agonist encounter can divert thymocytes into several unconventional T cell subsets, many of which exhibit regulatory properties. Unexpected findings indicate that agonist selection can drive the differentiation of interleukin 17– producing cells in the thymus.
PMCID: PMC3061549  PMID: 19767722
15.  Regulation of Th17 cells in the mucosal surfaces 
The mucosal surfaces represent the main intersection between jawed vertebrates and the environment. The mucosal surface of the intestine alone forms the largest surface that is exposed to exogenous antigens as well as the largest collection of lymphoid tissue in the body. Therefore, a protective immune activity must coexist with efficient regulatory mechanisms in order to maintain a health status of these organisms. The discovery of a new lineage of helper T cells that produce interleukin (IL)-17 has provided valuable new insight into host defense and the pathogenesis of inflammatory diseases at the mucosal surfaces. Of particular interest for these surfaces, it has been reported that peripherally-induced regulatory T cells and Th17 effector cells arise in a mutually exclusive fashion, depending on whether they are activated in the presence of TGF-β or TGF-β plus inflammatory cytokines such as IL-6. This review will address the protective and pathogenic roles of Th17 cells in the mucosal surfaces and potential regulatory mechanisms that control their development.
PMCID: PMC2679861  PMID: 19362732
Intestine; Lung; Mucosal; TH17; T regulatory cells
16.  More stories on Th17 cells 
Cell research  2009;19(4):399-411.
For more than two decades, immunologists have been using the so-called Th1/Th2 paradigm to explain most of the phenomena related to adaptive immunity. The Th1/Th2 paradigm implied the existence of two different, mutually regulated, CD4+ T helper subsets: Th1 cells, driving cell-mediated immune responses involved in tissue damage and infection against intracellular parasites; and Th2 cells that mediate IgE production and are particularly involved in eosinophilic inflammation, allergy and clearance of helminthic infections. A third member of the T helper set, IL-17-producing CD4+ T cells, now called Th17 cells, was recently described as a distinct lineage that does not share developmental pathways with either Th1 or Th2 cells. The Th17 subset has been linked to autoimmune disorders, being able to produce IL-17, IL-17F and IL-21 among other inflammatory cytokines. Interestingly, it has been reported that there is not only a cross-regulation among Th1, Th2 and Th17 effector cells but there is also a dichotomy in the generation of Th17 and T regulatory cells. Therefore, Treg and Th17 effector cells arise in a mutually exclusive fashion, depending on whether they are activated in the presence of TGF-β or TGF-β plus inflammatory cytokines such as IL-6. This review will address the discovery of the Th17 cells, and recent progress on their development and regulation.
PMCID: PMC2838708  PMID: 19255592
adaptive immunity; tolerance; IFN-γ; IL-4; IL-23; TGF-β
17.  IL-6 and STAT3 are required for survival of intestinal epithelial cells and development of colitis associated cancer 
Cancer cell  2009;15(2):103-113.
Colitis associated cancer (CAC) is the most serious complication of inflammatory bowel disease. Pro-inflammatory cytokines were suggested to regulate pre-neoplastic growth during CAC tumorigenesis. Interleukin 6 (IL-6) is a multifunctional NF-κB–regulated cytokine which acts on epithelial and immune cells. Using genetic tools we now demonstrate that IL-6 is a critical tumor promoter during early CAC tumorigenesis. In addition to enhancing proliferation of tumor initiating cells, IL-6 produced by lamina propria myeloid cells protects normal and pre-malignant intestinal epithelial cells (IEC) from apoptosis. The proliferative and survival effects of IL-6 are largely mediated by transcription factor STAT3, whose IEC-specific ablation has profound impact on CAC tumorigenesis. Thus, the NF-κB-IL-6-STAT3 cascade is an important regulator of the proliferation and survival of tumor initiating IEC.
PMCID: PMC2667107  PMID: 19185845
18.  From the diet to the nucleus: Vitamin A and TGF-β join efforts at the mucosal interface of the intestine 
Seminars in immunology  2008;21(1):14-21.
The Vitamin A metabolites, including retinoic acid (RA), form ligands for retinoic acid-related nuclear receptors and together they play pleiotropic roles in various biological processes. Recently, we described that RA also functions as a key modulator of transforming growth factor-beta (TGF-β)-driven immune deviation, capable of suppressing the differentiation of interleukin-17 secreting T helper cells (TH17) and conversely promoting the generation of Foxp3+ T regulatory (Treg) cells. This review will focus on the role of RA in the reciprocal TGF-β driven differentiation of TH17 and Treg and on the importance of such regulatory mechanism to control a functional immune system, in particular at the mucosal interface of the intestine.
PMCID: PMC2643336  PMID: 18809338
vitamin A; gut tropism; Foxp3; TH17; nuclear receptors
19.  TGFβ and Retinoic Acid Intersect in Immune-Regulation 
Cell Adhesion & Migration  2007;1(3):142-144.
Transforming growth factor (TGFβ) prevents TH1 and TH2 differentiation and converts naïve CD4 cells into Foxp3-expressing T regulatory (Treg) cell.1,2 In sharp contrast, in the presence of pro-inflammatory cytokines, including IL-6, TGFβ not only inhibits Foxp3 expression but also promotes the differentiation of pro-inflammatory IL17-producing CD4 effector T (TH17) cells.3–5
This reciprocal TGFβ-dependent differentiation imposes a critical dilemma between pro- and anti-inflammatory immunity and suggests that a sensitive regulatory mechanism must exist to control TGFβ-driven TH17 effector and Treg differentiation. A vitamin A metabolite, retinoic acid (RA), was recently identified as a key modulator of TGFβ-driven-immune deviation capable of suppressing TH17 differentiation while promoting Foxp3+Treg generation.6–10
PMCID: PMC2634017  PMID: 19262136
TGFβ; retinoic acid; Foxp3; TH17; IL-6; mucosal immune regulation; oral tolerance; transcription factors
20.  Oral tolerance in the absence of naturally occurring Tregs 
Journal of Clinical Investigation  2005;115(7):1923-1933.
Mucosal tolerance prevents pathological reactions against environmental and food antigens, and its failure results in exacerbated inflammation typical of allergies and asthma. One of the proposed mechanisms of oral tolerance is the induction of Tregs. Using a mouse model of hyper-IgE and asthma, we found that oral tolerance could be effectively induced in the absence of naturally occurring thymus-derived Tregs. Oral antigen administration prior to i.p. immunization prevented effector/memory Th2 cell development, germinal center formation, class switching to IgE, and lung inflammation. Oral exposure to antigen induced development of antigen-specific CD4+CD25+Foxp3+CD45RBlow cells that were anergic and displayed suppressive activity in vivo and in vitro. Oral tolerance to the Th2 allergic response was in large part dependent on TGF-β and independent of IL-10. Interestingly, Tregs were also induced by single i.p. immunization with antigen and adjuvant. However, unlike oral administration of antigen, which induced Tregs but not effector T cells, i.p. immunization led to the simultaneous induction of Tregs and effector Th2 cells displaying the same antigen specificity.
PMCID: PMC1142115  PMID: 15937545

Results 1-20 (20)