Search

Human dendritic cells (hDCs) produce IL-2 and express IL-2R α-chain (CD25), but the role of IL-2 in DC functions is not well defined. A recent study suggested that the main function of CD25 on hDCs was to transpresent IL-2 to activate T lymphocytes. Our results demonstrate the expression of the three chains of the IL-2R on hDCs and that IL-2 induces STAT5 phosphorylation. Interestingly, use of inhibitors of p-STAT5 revealed that IL-2 increases LPS-induced IFN-γ through STAT5 phosphorylation. Finally, we report that IL-2 increases the ability of hDCs to activate helpless CD8(+) T cells, most likely because of IL-2-triggered IFN-γ synthesis, as we previously described. For the first time, to our knowledge, we disclose that IL-2 induces monocyte-derived hDC's functional maturation and activation through IL-2R binding. Interestingly, our study suggests a direct effect of anti-CD25 mAbs on hDCs that may contribute to their clinical efficacy., (Copyright © 2014 by The American Association of Immunologists, Inc.)

Regulatory T cells (Treg) play a crucial role in controlling immunity and transplant rejection. Two main groups of Treg have been described: antigen-induced Treg (iTreg) and natural Treg (nTreg). The ways to induce and the mechanisms of action of Treg subsets remained ill defined, particularly for their effects on CD8(+) T cells. CD8(+) T cells are major agents in the rejection of allografts; the aim of this study is to investigate the effects exerted on CD8(+) T cells by human CD4(+) iTreg induced by mycophenolic acid-treated dendritic cells. iTreg suppress the proliferation of CD8(+) T cells by allogeneic cell-cell interaction with mature dendritic cells and irrespectively of the TCR specificity of the CD8(+) T cells and cell-cell contact of iTreg with CD8(+) T cells. In our model, this suppression is independent of the action of IL-10 and TGF-β1. iTreg were able to modify phenotype and inhibited IFN-γ and TNF-α secretion by CD8(+) T cells. Most interestingly, iTreg inhibit the synthesis of perforin and of granzymes A and B by CD8(+) T cells and impaired their cytotoxicity against allogeneic targets. In summary, our study showed the involvement of iTreg in the down-regulation of cytotoxic responses mediated by CD8(+) T cells in an allospecific context. Following studies that have shown the existence of a regulation control exerted by iTreg on CD4(+) T cells and dendritic cells, this work ultimately shows that this regulation can reach CD8(+) T-cell functions.

The high frequency of allogeneic reactive CD8(+) T cells in human and their resistance to immunosuppression might be one of the reasons why successful tolerance-inducing strategies in rodents have failed in primates. Studies on the requirement for T-helper cells in priming CD8(+) T-cell responses have led to disparate findings. Recent studies have reported CD8(+)-mediated allograft rejection independently of T-helper cells; however, the mechanisms that govern the activation of these T cells are far from being elucidated. In this study, we demonstrated that lipopolysaccharide-treated dendritic cells (DCs) were able to induce proliferation and cytotoxic activity of allogeneic CD8(+) T cells independently of CD4(+) T cells, while adding mycophenolic acid (MPA) to LPS abolished this capacity and resulted in anergic CD8(+) T cells that secreted high levels of interleukin-4 (IL-4), IL-5, IL-10, and transforming growth factor-β. Interestingly, we demonstrated that MPA inhibited the LPS-induced synthesis of tumor necrosis factor-α, IL-12, and interferon-γ (IFN-γ) in DCs. Importantly, we found that adding exogenous IFN-γ to MPA restored both the synthesis of cytokines and the ability to activate CD8(+) T cells. However, adding IL-12 or tumor necrosis factor-α had no effect. These results suggest that IFN-γ has an important role in licensing DCs to prime CD4-independent CD8 allogeneic T cells via an autocrine loop.

Mycophenolic acid (MPA) is an immunosuppressive drug which induces resistance to several maturation signals in human dendritic cells (DC) by unknown mechanisms. As mitogen-activated protein kinases (MAPK) are involved in the maturation process, we studied whether MPA affected p38MAPK and extracellular signal-regulated kinase (ERK1/2) in human DC. We first showed that MPA reduced TNFalpha-induced phenotype maturation, whereas it had no effect after LPS activation, suggesting that MPA preferentially affects the signaling pathway used by TNFalpha. We found that TNFalpha preferentially used p38MAPK to induce phenotype maturation in DC, whereas LPS preferentially activated NF-kappaB. Importantly, we showed that MPA more strongly inhibited p38MAPK phosphorylation induced by TNFalpha than by LPS. This difference in inhibition may therefore explain its different effect on DC phenotype. Interestingly, MPA inhibited the inflammatory cytokine synthesis and allostimulatory capacity induced by both stimuli. Exogenous guanosine antagonized the effect of MPA on the phenotype of TNFalpha-matured-DC as well as the IL-12p70 and IFN gamma secretion induced by both stimuli, without affecting p38MAPK phosphorylation. The action of MPA on human DC phenotype maturation appears mainly to be due to its ability to inhibit p38MAPK. Furthermore, the difference between LPS and TNFalpha emphasizes that the DC microenvironment strongly influences DC sensitivity to MPA., ((c) 2009 Elsevier Ltd. All rights reserved.)

Depending on their degree of maturation, costimulatory molecule expression, and cytokine secretion, dendritic cells (DC) can induce immunity or tolerance. DC treated with mycophenolic acid during their maturation (MPA-DC) have a regulatory phenotype and may therefore provide a new approach to induce allograft tolerance. Purified CD4(+) T cells stimulated in a human in vitro model of mixed culture by allogeneic MPA-DC displayed much weaker proliferation than T cells activated by mature DC and were anergic. This hyporesponsiveness was alloantigen-specific. Interestingly, T cells stimulated by MPA-DC during long-term coculture in four 7-day cycles displayed potent, suppressive activity, as revealed by marked inhibition of the proliferation of naive and preactivated control T cells. These regulatory T cells (Tregs) appeared to have antigen specificity and were contact-dependent. Tregs induced by MPA-DC were CD25(+)glucocorticoid-induced TNFR(+)CTLA-4(+)CD95(+), secreted IL-5 and large amounts of IL-10 and TGF-beta, and displayed enhanced forkhead box p3 expression. These results obtained in vitro demonstrate that human MPA-DC can induce allospecific Tregs that may be exploited in cell therapy to induce allograft tolerance.

• Human monocytes-derived dendritic cells submitted to extracellular Na + concentrations up to 200 mM remain viable and maintain the expression of specific DC markers and not that of macrophages. • High NaCl concentrations inhibited the maturation of human dendritic cells, chemotaxis toward CCL19 and production of pro-inflammatory cytokines and ROS in response to LPS. • High NaCl concentrations inhibited T -cell allostimulatory capacity of human dendritic cells. • High NaCl concentrations triggered the activation of SGK1 and ERK1/2 kinases. Recent evidence showed that in response to elevated sodium dietary intakes, many body tissues retain Na+ ions for long periods of time and can reach concentrations up to 200 mM. This could modulate the immune system and be responsible for several diseases. However, studies brought contrasted results and the effects of external sodium on human dendritic cell (DC) responses to danger signals remain largely unknown. Considering their central role in triggering T cell response, we tested how NaCl-enriched medium influences human DCs properties. We found that DCs submitted to high extracellular Na+ concentrations up to 200 mM remain viable and maintain the expression of specific DC markers, however, their maturation, chemotaxis toward CCL19, production of pro-inflammatory cytokines and ROS in response to LPS were also partially inhibited. In line with these results, the T -cell allostimulatory capacity of DCs was also inhibited. Finally, our data indicate that high NaCl concentrations triggered the phosphorylation of SGK1 and ERK1/2 kinases. These results raised the possibility that the previously reported pro-inflammatory effects of high NaCl concentrations on T cells might be counterbalanced by a downregulation of DC activation. [ABSTRACT FROM AUTHOR]