Key Points CD1c+ DC but not BDCA-3+ DC or other antigen-presenting cells secrete high amounts of bioactive IL-12. CD1c+ DC efficiently cross-present antigens, prime CD8+ T cells, and induce the highest levels of cytotoxic molecules.

Sil.G. helped in the execution of the mouse experiments; B.F., M.M. and Gr.P. performed 16s rRNA metagenomic analysis; L.M. and W.V. designed and carried out histological analyses. G.N. performed ex-vivo stimulation of human colonic mucosa experiments; A.B. performed confocal analyses; J.T. executed metabolomic analyses; B.O. helped in the execution of in vitro experiments; K.A. and K.H. isolated F.PB1 and carried out GF experiments; S.A. and S.G. set up F. PB1 growth and supernatant production; S.C. set up H. biformis and L. lactis growth and supernatant production; G.F. performed FACS analyses; F.A. and N.S. performed phylogenetic analysis and human CRC dataset interrogation; G.P. participated with ideas and results interpretation; M.R. ideated the study, coordinated the work, and wrote the manuscript.

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.

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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.

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.

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. Keywords:Cross presentation/priming r cytotoxic T cells r Dendritic cells r Interleukin-10 r Regulatory T cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site Eur. J. Immunol. 2016Immunol. . 46: 1622Immunol. -1632 Adaptive immunity 1623 IntroductionInterleukin-10 is a tolerogenic cytokine, since it blocks the production of proinflammatory cytokines by myeloid cells [1] and inhibits the upregulation of MHC and T-cell costimulatory molecules. IL-10 can also act directly on T cells, and prevents the expansion of pathogenic CD4 + effector T cells in the intestine [2]. Moreover, IL-10 was shown to promote suppressive functions of Foxp3 + regulatory T cells [3]. Consistently, genetic defects in the IL-10/IL-10R pathway lead to spontaneous colitis in mice [4] and severe intestinal inflammation in humans [5]. Nevertheless, IL-10 promotes CTL responses [6][7][8] and memory generation [9], and contributes to CD8 + T-cell-mediated autoimmune diabetes in Here, we analyzed the requirements and the functional relevance of IL-10 production by human DC subsets in T cell responses. We found that IL-10 production was restricted to CD1c + DCs and selectively blocked the priming of low-affinity CTL. Moreover, IL-10 enhanced the homeostatic proliferation of established memory CTL. Results Different regulation of IL-10 production in human DCs and monocytesTo compare the IL-10 producing capacities of human APC, we stimulated FACS-purified DC [24] and monocyte subsets (Supporting Information Fig. 1A) with Zymosan ( Fig. 1A), which induces IL-10 in all mDC subsets in mice [26,27]. CD1c + DCs ...

Intestinal Th17 cell pathogenicity is associated with IFNγ production, which directly affects intestinal permeability through the disruption of epithelial tight junctions.