The immune tolerance to rat kidney allografts induced by a perioperative treatment with anti-CD28 Abs is associated with a severe unresponsiveness of peripheral blood cells to donor Ags. In this model, we identified an accumulation in the blood of CD3−class II−CD11b+CD80/86+ plastic-adherent cells that additionally expressed CD172a as well as other myeloid markers. These cells were able to inhibit proliferation, but not activation, of effector T cells and to induce apoptosis in a contact-dependent manner. Their suppressive action was found to be under the control of inducible NO synthase, an enzyme also up-regulated in tolerated allografts. Based on these features, these cells can be defined as myeloid-derived suppressor cells (MDSC). Interestingly, CD4+CD25highFoxP3+ regulatory T cells were insensitive in vitro to MDSC-mediated suppression. Although the adoptive transfer of MDSC failed to induce kidney allograft tolerance in recently transplanted recipients, the maintenance of tolerance after administration of anti-CD28 Abs was found to be dependent on the action of inducible NO synthase. These results suggest that increased numbers of MDSC can inhibit alloreactive T cell proliferation in vivo and that these cells may participate in the NO-dependent maintenance phase of tolerance.

No abstract

Human blood DCs encompass pDCs and two subsets of mDCs: CD1c(+) mDCs and CD141(+) mDCs. The rare CD141(+) DC population is thought to be the equivalent of mouse CD8α(+) cDCs that play a significant role in antigen cross-presentation. Here, we analyzed by Q-PCR TLR1-10 expression in blood DC subsets. Whereas CD1c(+) DCs express all TLR except TLR9, CD141(+) DCs present a more restricted pattern with high expression of TLR3 and -10, expression of TLR1,-2, -6, and -8, and lack of TLR4, -5, -7, and -9. The in vitro analysis of isolated mDC subset reponsiveness to an extensive panel of TLR ligands confirmed these results, with CD141(+) DCs responding only to TLR1/2, -3, and -7/8. The cytokine/chemokine production profile of isolated CD141(+) DCs was also more restricted, as they produced mainly proinflammatory cytokines but no IL-12 and to a lower level, in comparison with CD1c(+) DCs, except for CXCL10, CCL5, and IFN-β. In contrast, with the use of a whole blood assay, we found that CD141(+) DCs produce IL-12 in response to TLR1/2, -3, and more surprisingly, -9. Finally, both mDC subsets are potent inducers of Th1 response, particularly after TLR3 triggering. Taken together, these data confirmed functional differences between blood mDC subsets. The major response of CD141(+) mDCs to TLR3 ligand and their cytokine production pattern suggest a role for these cells in antiviral immunity.

IL-22 is mainly produced at barrier surfaces by T cells and innate lymphoid cells and is crucial to maintain epithelial integrity. However, dysregulated IL-22 action leads to deleterious inflammation and is involved in diseases such as psoriasis, intestinal inflammation and cancer. IL-22BP is a soluble inhibitory IL-22 receptor and may represent a crucial regulator of IL-22. We show both in rats and mice that, in the steady state, the main source of IL-22BP is constituted by a subset of conventional dendritic cells (DC) in lymphoid and non lymphoid tissues. In mouse intestine, IL-22BP was specifically expressed in lamina propria CD103+CD11b+ DC. In humans, IL-22BP was expressed in immature monocyte-derived DC (MDDC) and strongly induced by retinoic acid (RA) but dramatically reduced upon maturation. Our data suggest that a subset of immature DC may actively participate in the regulation of IL-22 activity in the gut by producing high levels of IL-22BP.

The authors demonstrate an effect of allogeneic exosomes on the modulation of immune responses in vivo, suggesting that, like donor cells, exosomes can stimulate or regulate antigen-specific immune responses.

We recently reported that splenic dendritic cells (DC) in rats can be separated into CD4+ and CD4− subsets and that the CD4− subset exhibited a natural cytotoxic activity in vitro against tumor cells. Moreover, a recent report suggests that CD4− DC could have tolerogenic properties in vivo. In this study, we have analyzed the phenotype and in vitro T cell stimulatory activity of freshly isolated splenic DC subsets. Unlike the CD4− subset, CD4+ splenic DC expressed CD5, CD90, and signal regulatory protein α molecules. Both fresh CD4− and CD4+ DC displayed an immature phenotype, although CD4+ cells constitutively expressed moderate levels of CD80. The half-life of the CD4−, but not CD4+ DC in vitro was extremely short but cells could be rescued from death by CD40 ligand, IL-3, or GM-CSF. The CD4− DC produced large amounts of the proinflammatory cytokines IL-12 and TNF-α and induced Th1 responses in allogeneic CD4+ T cells, whereas the CD4+ DC produced low amounts of IL-12 and no TNF-α, but induced Th1 and Th2 responses. As compared with the CD4+ DC that strongly stimulated the proliferation of purified CD8+ T cells, the CD4− DC exhibited a poor CD8+ T cell stimulatory capacity that was substantially increased by CD40 stimulation. Therefore, as previously shown in mice and humans, we have identified the existence of a high IL-12-producing DC subset in the rat that induces Th1 responses. The fact that both the CD4+ and CD4− DC subsets produced low amounts of IFN-α upon viral infection suggests that they are not related to plasmacytoid DC.

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We have previously shown that human monocyte-derived dendritic cells (DC) express indoleamine 2,3-dioxygenase (IDO), as well as several other enzymes of the kynurenine pathway at the mRNA level upon maturation. The tolerogenic mechanisms of this pathway remain unclear. Here we show that LPS-treated DC metabolize tryptophan as far as quinolinate. We found that IDO contributes to LPS and TNF-a + poly(I:C)-induced DC maturation since IDO inhibition using two different inhibitors impairs DC maturation. IDO knock-down using short-hairpin RNA also led to diminished LPSinduced maturation. In line with these results, the tryptophan-derived catabolites 3-hydroxyanthranilic acid and 3-hydroxykynurenine increased maturation of LPStreated DC. Concerning the molecular mechanisms of this effect, IDO acts as an intermediate pathway in LPS-induced production of reactive oxygen species and NF-jB activation, two processes that lead to DC maturation. Finally, we show that mature DC expand CD4 + CD25 high regulatory T cells in an IDO-dependent manner. In conclusion, we show that IDO constitutes an intermediate pathway in DC maturation leading to expansion of CD4 + CD25 high regulatory T cells.