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1.
Nat Microbiol ; 5(3): 511-524, 2020 03.
Article in English | MEDLINE | ID: mdl-31988379

ABSTRACT

The microbiota has been shown to promote intestinal tumourigenesis, but a possible anti-tumourigenic effect has also been postulated. Here, we demonstrate that changes in the microbiota and mucus composition are concomitant with tumourigenesis. We identified two anti-tumourigenic strains of the microbiota-Faecalibaculum rodentium and its human homologue, Holdemanella biformis-that are strongly under-represented during tumourigenesis. Reconstitution of ApcMin/+ or azoxymethane- and dextran sulfate sodium-treated mice with an isolate of F. rodentium (F. PB1) or its metabolic products reduced tumour growth. Both F. PB1 and H. biformis produced short-chain fatty acids that contributed to control protein acetylation and tumour cell proliferation by inhibiting calcineurin and NFATc3 activation in mouse and human settings. We have thus identified endogenous anti-tumourigenic bacterial strains with strong diagnostic, therapeutic and translational potential.


Subject(s)
Firmicutes/physiology , Gastrointestinal Microbiome/physiology , Intestinal Neoplasms/microbiology , Intestines/microbiology , Adult , Aged , Animals , Cell Proliferation/drug effects , Colonic Neoplasms/microbiology , Colonic Neoplasms/therapy , DNA, Bacterial/genetics , DNA, Bacterial/isolation & purification , Fatty Acids, Volatile/metabolism , Female , Firmicutes/isolation & purification , Humans , In Situ Hybridization, Fluorescence , Intestinal Neoplasms/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Middle Aged , RNA, Bacterial/genetics , RNA, Bacterial/isolation & purification
2.
Nat Commun ; 9(1): 5184, 2018 12 05.
Article in English | MEDLINE | ID: mdl-30518790

ABSTRACT

Alteration of the gut microbiota has been associated with different gastrointestinal disorders. Normobiosis restoration by faecal microbiota transplantation (FMT) is considered a promising therapeutic approach, even if the mechanisms underlying its efficacy are at present largely unknown. Here we sought to elucidate the functional effects of therapeutic FMT administration during experimental colitis on innate and adaptive immune responses in the intestinal mucosa. We show that therapeutic FMT reduces colonic inflammation and initiates the restoration of intestinal homeostasis through the simultaneous activation of different immune-mediated pathways, ultimately leading to IL-10 production by innate and adaptive immune cells, including CD4+ T cells, iNKT cells and Antigen Presenting Cells (APC), and reduces the ability of dendritic cells, monocytes and macrophages to present MHCII-dependent bacterial antigens to colonic T cells. These results demonstrate the capability of FMT to therapeutically control intestinal experimental colitis and poses FMT as a valuable therapeutic option in immune-related pathologies.


Subject(s)
Colitis/therapy , Fecal Microbiota Transplantation , Interleukin-10/immunology , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology , Adaptive Immunity , Animals , Antigen-Presenting Cells/immunology , CD4-Positive T-Lymphocytes/immunology , Colitis/genetics , Colitis/immunology , Colitis/microbiology , Dendritic Cells/immunology , Disease Models, Animal , Female , Gastrointestinal Microbiome , Humans , Immunity, Innate , Interleukin-10/genetics , Macrophages/immunology , Male , Mice , Mice, Inbred C57BL , Natural Killer T-Cells/immunology
3.
J Crohns Colitis ; 12(8): 981-992, 2018 Jul 30.
Article in English | MEDLINE | ID: mdl-29697763

ABSTRACT

BACKGROUND AND AIMS: T helper 17 [Th17] cells are crucially involved in the immunopathogenesis of inflammatory bowel diseases in humans. Nevertheless, pharmacological blockade of interleukin 17A [IL17A], the Th17 signature cytokine, yielded negative results in patients with Crohn's disease [CD], and attempts to elucidate the determinants of Th17 cells' pathogenicity in the gut have so far proved unsuccessful. Here, we aimed to identify and functionally validate the pathogenic determinants of intestinal IL-17-producing T cells. METHODS: In vivo-generated murine intestinal IL-17-producing T cells were adoptively transferred into immunodeficient Rag1-/- recipients to test their pathogenicity. Human IL-17, IFNγ/IL-17, and IFNγ actively secreting T cell clones were generated from lamina propria lymphocytes of CD patients. The pathogenic activity of intestinal IL-17-producing T cells against the intestinal epithelium was evaluated. RESULTS: IL-17-producing cells with variable colitogenic activity can be generated in vivo using different experimental colitis models. The pathogenicity of IL-17-secreting cells was directly dependent on their IFNγ secretion capacity, as demonstrated by the reduced colitogenic activity of IL-17-secreting cells isolated from IFNγ-/- mice. Moreover, IFNγ production is a distinguished attribute of CD-derived lamina propria Th17 cells. IFNγ secretion by CD-derived IL-17-producing intestinal clones is directly implicated in the epithelial barrier disruption through the modulation of tight junction proteins. CONCLUSIONS: Intestinal Th17 cell pathogenicity is associated with IFNγ production, which directly affects intestinal permeability through the disruption of epithelial tight junctions.


Subject(s)
Colitis/immunology , Crohn Disease/pathology , Interferon-gamma/metabolism , Intestinal Mucosa/pathology , Th17 Cells/immunology , Th17 Cells/metabolism , Adult , Aged , Animals , Clone Cells/immunology , Clone Cells/metabolism , Crohn Disease/immunology , Crohn Disease/metabolism , Female , Homeodomain Proteins/genetics , Humans , Interferon-gamma/genetics , Interleukin-17/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Male , Mice , Mice, Knockout , Middle Aged , Permeability , Th1 Cells/metabolism , Tight Junctions/metabolism
4.
Clin Transl Gastroenterol ; 7(7): e182, 2016 Jul 14.
Article in English | MEDLINE | ID: mdl-27415620

ABSTRACT

OBJECTIVES: To provide a functional and phenotypic characterization of immune cells infiltrating small intestinal mucosa during non-IPEX autoimmune enteropathy (AIE), as to gain insights on the pathogenesis of this clinical condition. METHODS: Duodenal biopsies from a patient with AIE at baseline and following drug-induced remission were analyzed by immunohistochemistry, immunofluorescence, and flow cytometry, and results were compared with those obtained from patients with active celiac disease, ileal Crohn's disease and healthy controls. Lamina propria (LP) and intraepithelial (IELs) lymphocytes from AIE and controls were analyzed for mechanisms regulating cytokine production. Foxp3 expression and suppressive functions of LP regulatory T cells (Tregs) were analyzed. RESULTS: The quantitative deficit of Foxp3 expression in Tregs in AIE associates with unrestrained IL-17 production by IELs. Interleukin (IL)-17-producing IELs were rare in the uninflamed duodenum and in the ileum of Crohn's disease patients, and disappeared upon drug-induced AIE remission. IL-17 upregulation in CD4(+)IELs and CD4(+)LP T cells had different requirements for pro-inflammatory cytokines. Moreover, transforming growth factor-ß (TGF-ß) selectively enhanced IL-17 production by CD8(+)IELs. Intriguingly, although Foxp3(low)Tregs in AIE were poorly suppressive, they could upregulate GARP-LAP/TGF-ß surface expression and enhanced IL-17 production selectively by CD8(+)IELs. Finally, phosphorylated Smad2/3 was detectable in duodenal CD8(+) lymphocytes in active AIE in situ, indicating that they received signals from the TGF-ß receptor in vivo. CONCLUSIONS: AIE is characterized by the appearance of unconventional IL-17-producing IELs, which could be generated locally by pro-inflammatory cytokines and TGF-ß. These results suggest that Foxp3(+)Tregs and Treg-derived TGF-ß regulate IL-17 production by IELs in the small intestine and in AIE.

5.
Eur J Immunol ; 46(7): 1622-32, 2016 07.
Article in English | MEDLINE | ID: mdl-27129615

ABSTRACT

IL-10 is an anti-inflammatory cytokine that inhibits maturation and cytokine production of dendritic cells (DCs). Although mature DCs have the unique capacity to prime CD8(+) CTL, IL-10 can promote CTL responses. To understand these paradoxic findings, we analyzed the role of IL-10 produced by human APC subsets in T-cell responses. IL-10 production was restricted to CD1c(+) DCs and CD14(+) monocytes. Interestingly, it was differentially regulated, since R848 induced IL-10 in DCs, but inhibited IL-10 in monocytes. Autocrine IL-10 had only a weak inhibitory effect on DC maturation, cytokine production, and CTL priming with high-affinity peptides. Nevertheless, it completely blocked cross-priming and priming with low-affinity peptides of a self/tumor-antigen. IL-10 also inhibited CD1c(+) DC-induced CD4(+) T-cell priming and enhanced Foxp3 induction, but was insufficient to induce T-cell IL-10 production. CD1c(+) DC-derived IL-10 had also no effect on DC-induced secondary expansions of memory CTL. However, IL-15-driven, TCR-independent proliferation of memory CTL was enhanced by IL-10. We conclude that DC-derived IL-10 selects high-affinity CTL upon priming. Moreover, IL-10 preserves established CTL memory by enhancing IL-15-dependent homeostatic proliferation. These combined effects on CTL priming and memory maintenance provide a plausible mechanism how IL-10 promotes CTL responses in humans.


Subject(s)
Antigens, CD1/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Glycoproteins/metabolism , Immunologic Memory/immunology , Interleukin-10/metabolism , Lymphocyte Activation/immunology , Antigen Presentation/immunology , Autocrine Communication/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/cytology , Cross-Priming/immunology , Cytokines/metabolism , HLA-A Antigens/immunology , HLA-A Antigens/metabolism , Humans , Inflammation Mediators/metabolism , Monocytes/immunology , Monocytes/metabolism
6.
Cytokine Growth Factor Rev ; 30: 87-93, 2016 08.
Article in English | MEDLINE | ID: mdl-26980675

ABSTRACT

Interleukin-10 (IL-10) is known to be a tolerogenic cytokine since it inhibits pro-inflammatory cytokine production and T cell stimulatory capacities of myeloid cells, such as macrophages and dendritic cells. In particular, it has a non-redundant tolerogenic role in intestinal immune homeostasis, since mice and patients with genetic defects in the IL-10/IL-10R pathway develop spontaneously colitis in the presence of a normal intestinal flora. However, IL-10 is also a growth and differentiation factor for B-cells, can promote autoantibody production and has consequently a pathogenic role in systemic lupus erythematosus. Moreover, IL-10 can promote cytotoxic T-cell (CTL) responses and this immunogenic activity might be relevant in type-1 diabetes and anti-tumor immune responses. This review summarizes these paradoxic effects of IL-10 on different types of immune responses, and proposes that different cellular sources of IL-10, in particular IL-10-secreting helper and regulatory T-cells, have different effects on B-cell and CTL responses. Based on this concept we discuss the rationales for targeting the IL-10 pathway in immune-mediated diseases and cancer.


Subject(s)
Interleukin-10/immunology , Lupus Erythematosus, Systemic/immunology , Neoplasms/immunology , Animals , B-Lymphocytes/immunology , Homeostasis , Humans , Intestines/immunology , T-Lymphocytes/immunology
7.
Front Immunol ; 6: 527, 2015.
Article in English | MEDLINE | ID: mdl-26528289

ABSTRACT

Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that have a key role in immune responses because they bridge the innate and adaptive arms of the immune system. They mature upon recognition of pathogens and upregulate MHC molecules and costimulatory receptors to activate antigen-specific CD4(+) and CD8(+) T cells. It is now well established that DCs are not a homogeneous population but are composed of different subsets with specialized functions in immune responses to specific pathogens. Upon viral infections, plasmacytoid DCs (pDCs) rapidly produce large amounts of IFN-α, which has potent antiviral functions and activates several other immune cells. However, pDCs are not particularly potent APCs and induce the tolerogenic cytokine IL-10 in CD4(+) T cells. In contrast, myeloid DCs (mDCs) are very potent APCs and possess the unique capacity to prime naive T cells and consequently to initiate a primary adaptive immune response. Different subsets of mDCs with specialized functions have been identified. In mice, CD8α(+) mDCs capture antigenic material from necrotic cells, secrete high levels of IL-12, and prime Th1 and cytotoxic T-cell responses to control intracellular pathogens. Conversely, CD8α(-) mDCs preferentially prime CD4(+) T cells and promote Th2 or Th17 differentiation. BDCA-3(+) mDC2 are the human homologue of CD8α(+) mDCs, since they share the expression of several key molecules, the capacity to cross-present antigens to CD8(+) T-cells and to produce IFN-λ. However, although several features of the DC network are conserved between humans and mice, the expression of several toll-like receptors as well as the production of cytokines that regulate T-cell differentiation are different. Intriguingly, recent data suggest specific roles for human DC subsets in immune responses against individual pathogens. The biology of human DC subsets holds the promise to be exploitable in translational medicine, in particular for the development of vaccines against persistent infections or cancer.

8.
J Immunol ; 193(7): 3322-31, 2014 Oct 01.
Article in English | MEDLINE | ID: mdl-25172491

ABSTRACT

IL-21 promotes Th17 differentiation, and Th17 cells that upregulate T-bet, IFN-γ, and GM-CSF drive experimental autoimmune diseases in mice. Anti-IL-21 treatment of autoimmune patients is therefore a therapeutic option, but the role of IL-21 in human T cell differentiation is incompletely understood. IL-21 was produced at high levels by human CD4(+) central memory T cells, suggesting that it is associated with early T cell differentiation. Consistently, it was inhibited by forced expression of T-bet or RORC2, the lineage-defining transcription factors of Th1 and Th17 effector cells, respectively. Although IL-21 was efficiently induced by IL-12 in naive CD4(+) T cells, it inhibited the generation of Th1 effector cells in a negative feedback loop. IL-21 was also induced by IL-6 and promoted Th17 differentiation, but it was not absolutely required. Importantly, however, IL-21 promoted IL-10 secretion but inhibited IFN-γ and GM-CSF production in developing Th17 cells, and consequently prevented the generation of polyfunctional Th1/17 effector cells. Moreover, in Th17 memory cells, IL-21 selectively inhibited T-bet upregulation and GM-CSF production. In summary, IL-21 is a central memory T cell-associated cytokine that promotes Th17 differentiation and IL-10 production, but inhibits the generation of potentially pathogenic Th1/17 effector cells. These findings shed new light on the role of IL-21 in T cell differentiation, and have relevant implications for anti-IL-21 therapy of autoimmune diseases.


Subject(s)
Autoimmune Diseases/immunology , Cell Differentiation/immunology , Immunologic Memory , Interleukins/immunology , Th1 Cells/immunology , Th17 Cells/immunology , Animals , Autoimmune Diseases/pathology , Autoimmune Diseases/therapy , Female , Humans , Interleukin-10/immunology , Interleukin-12/immunology , Interleukin-6/immunology , Male , Mice , Nuclear Receptor Subfamily 1, Group F, Member 3/immunology , T-Box Domain Proteins/immunology , Th1 Cells/pathology , Th17 Cells/pathology , Up-Regulation/immunology
9.
Blood ; 122(6): 932-42, 2013 Aug 08.
Article in English | MEDLINE | ID: mdl-23794066

ABSTRACT

Dendritic cells (DC) have the unique capacities to induce primary T-cell responses. In mice, CD8α(+)DC are specialized to cross-prime CD8(+) T cells and produce interleukin-12 (IL-12) that promotes cytotoxicity. Human BDCA-3(+)DC share several relevant characteristics with CD8α(+)DC, but the capacities of human DC subsets to induce CD8(+) T-cell responses are incompletely understood. Here we compared CD1c(+) myeloid DC (mDC)1, BDCA-3(+)mDC2, and plasmacytoid DC (pDC) in peripheral blood and lymphoid tissues for phenotype, cytokine production, and their capacities to prime cytotoxic T cells. mDC1 were surprisingly the only human DC that secreted high amounts of IL-12p70, but they required combinational Toll-like receptor (TLR) stimulation. mDC2 and pDC produced interferon-λ and interferon-α, respectively. Importantly, mDC1 and mDC2 required different combinations of TLR ligands to cross-present protein antigens to CD8(+) T cells. pDC were inefficient and also expressed lower levels of major histocompatibility complex and co-stimulatory molecules. Nevertheless, all DC induced CD8(+) memory T-cell expansions upon licensing by CD4(+) T cells, and primed naive CD8(+) T cells following appropriate TLR stimulation. However, because mDC1 produced IL-12, they induced the highest levels of cytotoxic molecules. In conclusion, CD1c(+)mDC1 are the relevant source of IL-12 for naive T cells and are fully equipped to cross-prime cytotoxic T-cell responses.


Subject(s)
Antigens, CD1/metabolism , Dendritic Cells/cytology , Glycoproteins/metabolism , Interleukin-12/metabolism , T-Lymphocytes, Cytotoxic/cytology , Animals , Antigen Presentation , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Cell Proliferation , Cell Separation , Cytokines/metabolism , Dendritic Cells/metabolism , Humans , Immunologic Memory , Interferon-alpha/metabolism , Interferon-gamma/metabolism , Lymphocyte Activation , Mice , Phenotype , Toll-Like Receptors/metabolism
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