HIV elite controllers (EC) are a rare group of HIV-infected patients who are able to maintain undetectable viral loads during a long period of time in the absence of antiretroviral treatment. Adaptive immunity and host genetic factors, although implicated, do not entirely explain this phenomenon. On the other hand, plasmacytoid dendritic cells (pDCs) are the principal type I interferon (IFN) producers in response to viral infection, and it is unknown whether pDCs are involved in the control of HIV infection in EC. In our study, we analyzed peripheral pDC levels and IFN-␣ production by peripheral blood mononuclear cells (PBMCs) in EC compared to other groups of HIV-infected patients, the ability of pDCs to reduce HIV production in vitro, and the mechanisms potentially involved. We showed preserved pDC counts and IFN-␣ production in EC. We also observed a higher capacity of pDCs from EC to reduce HIV production and to induce T cell apoptosis, whereas pDCs from viremic patients barely responded without previous Toll-like receptor 9 (TLR-9) stimulus. The preserved functionality of pDCs from EC to reduce viral production may be one of the mechanisms involved in the control of HIV viremia in these subjects. These results demonstrate the importance of innate immunity in HIV pathogenesis, and an understanding of pDC mechanisms would be helpful for the design of new therapies.

Significance Immunoregulatory poperties have been principally ascribed to various mature immune cell types, including regulatory B cells. An immature B-cell progenitor population endowed with suppressive properties per se or after differentiation into more mature regulatory B cells has not been demonstrated as yet. We now describe a pro–B-cell progenitor population that emerged upon stimulation with the Toll-like receptor-9 ligand CpG and prevented disease upon adoptive transfer into autoimmune type 1 diabetes-prone mice. Effector T cells were the target of immunoregulatory pro-B cells and of their mature progeny. Such protective pro-B cells could be instrumental for cell therapy of autoimmune diseases.

BackgroundDengue displays a broad spectrum of clinical manifestations that may vary from asymptomatic to severe and even fatal features. Plasma leakage/hemorrhages can be caused by a cytokine storm induced by monocytes and dendritic cells during dengue virus (DENV) replication. Plasmacytoid dendritic cells (pDCs) are innate immune cells and in response to virus exposure secrete IFN-α and express membrane TRAIL (mTRAIL). We aimed to characterize pDC activation in dengue patients and their function under DENV-2 stimulation in vitro.Methods & FindingsFlow cytometry analysis (FCA) revealed that pDCs of mild dengue patients exhibit significantly higher frequencies of mTRAIL compared to severe cases or healthy controls. Plasma levels of IFN-α and soluble TRAIL are increased in mild compared to severe dengue patients, positively correlating with pDC activation. FCA experiments showed that in vitro exposure to DENV-2 induced mTRAIL expression on pDC. Furthermore, three dimension microscopy highlighted that TRAIL was relocalized from intracellular compartment to plasma membrane. Chloroquine treatment inhibited DENV-2-induced mTRAIL relocalization and IFN-α production by pDC. Endosomal viral degradation blockade by chloroquine allowed viral antigens detection inside pDCs. All those data are in favor of endocytosis pathway activation by DENV-2 in pDC. Coculture of pDC/DENV-2-infected monocytes revealed a dramatic decrease of antigen detection by FCA. This viral antigens reduction in monocytes was also observed after exogenous IFN-α treatment. Thus, pDC effect on viral load reduction was mainly dependent on IFN-α productionConclusionsThis investigation characterizes, during DENV-2 infection, activation of pDCs in vivo and their antiviral role in vitro. Thus, we propose TRAIL-expressing pDCs may have an important role in the outcome of disease.

We demonstrate that, in response to HIV, pDCs from controller patients produce IFN-α, express membrane TRAIL, and induce apoptosis of T-cell lines.

A recent report demonstrated that free human T-cell leukemia virus 1 (HTLV-1) could infect plasmacytoid dendritic cells (pDCs). The major role of pDCs is to secrete massive levels of interferon-␣ (IFN-␣) upon virus exposure; however, the induction of IFN-␣ by HTLV-1 remains unknown. We demonstrate here that cellfree HTLV-1 generated a pDC innate immune response by producing massive levels of IFN-␣ that were inhibited by anti-HTLV-1 antibodies. HTLV-1 induced costimulatory molecules and rapid expression of the apoptotic ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Furthermore, HTLV-1 stimulated pDC-induced apoptosis of CD4 ؉ T cells expressing DR5, transforming pDCs into IFN-producing killer pDCs. We also observed that an endosomal acidification inhibitor and a Toll-like receptor-7 (TLR7)-specific blocker drastically inhibited pDC response to HTLV-1. Three-dimensional microscopy analysis revealed that unstimulated pDCs were "dormant" IFNproducing killer pDCs with high levels of intracellular TRAIL that could be rapidly mobilized to the surface in response to TLR7 activation. Inhibition of viral degradation in endosomes by chloroquine maintained viral integrity, allowing virus detection by 3-dimensional microscopy. We demonstrate that pDCs respond to cell-free HTLV-1 by producing high levels of IFN-␣ and by mobilizing TRAIL on cell surface after TLR7 triggering. This is the first demonstration of an innate immune response induced by free HTLV-1. (Blood. 2010;115:2177-2185) IntroductionHuman T-cell leukemia virus 1 (HTLV-1), the first characterized human retrovirus, 1 has been identified as the causative agent for adult T-cell leukemia/lymphoma (ATLL) 2,3 and HTLV-1-associated myelopathy/tropical spastic paraparesis, 4 uveitis, and infective dermatitis in children. 5 HTLV-1 virions infect CD4 ϩ T cells, which represent the main target for HTLV-1 infection in peripheral blood. HTLV-1-associated diseases occur after long periods of virus latency. 6 For years it has been thought that unlike other retroviruses, free virions were poorly infectious. 7 However, Jones et al 8 recently reported that freshly isolated myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) are efficiently and productively infected by cell-free HTLV-1. Furthermore, infected mDCs and pDCs were able to transfer virions to autologous CD4 ϩ T cells, clearly demonstrating that cell-free HTLV-1 can be infectious and target DCs. 8 pDCs participate in innate and adaptive immunity, 9,10 are located in blood and lymphoid organs, 10,11 and produce up to 1000-fold more interferon-␣ (IFN-␣) than other cell types in response to virus exposure. 12 Three molecules have been characterized for HTLV-1 entry into cells, heparan sulfate proteoglycans 13 and BDCA-4 (also called neuropilin-1) 14 for the initial virus binding to target cells 15 and glucose transporter 1 for the postattachment and the viral fusion. 16,17 Interestingly, BDCA-4 is expressed by mDC and T cells 18,19 but cells expressing the greatest level of BDCA...

The influence of signals perceived by immature B cells during their development in bone marrow on their subsequent functions as mature cells are poorly defined. Here, we show that bone marrow cells transiently stimulated in vivo or in vitro through the Toll-like receptor 9 generate proB cells (CpG-proBs) that interrupt experimental autoimmune encephalomyelitis (EAE) when transferred at the onset of clinical symptoms. Protection requires differentiation of CpG-proBs into mature B cells that home to reactive lymph nodes, where they trap T cells by releasing the CCR7 ligand, CCL19, and to inflamed central nervous system, where they locally limit immunopathogenesis through interleukin-10 production, thereby cooperatively inhibiting ongoing EAE. These data demonstrate that a transient inflammation at the environment, where proB cells develop, is sufficient to confer regulatory functions onto their mature B-cell progeny. In addition, these properties of CpG-proBs open interesting perspectives for cell therapy of autoimmune diseases.

G-CSF prevents type 1 diabetes in the NOD mouse by promoting the local recruitment of T regulatory cells (Tregs). This is an indirect effect because adoptive transfer of G-CSF–induced tolerogenic dendritic cells (DCs) promotes Treg accumulation. However, the identity of the particular DC subset and the molecule(s) mediating this effect remain unknown. We demonstrate in this study that the adoptive transfer of CD11chighCD8α− DCs isolated from pegylated G-CSF (pegG-CSF) recipients, but not that of other DC subtypes, enhanced the pancreatic recruitment of CD4+CD25+Foxp3+ Tregs, which generated increased amounts of TGF-β. Likewise, only CD11chighCD8α− DCs from pegG-CSF recipients secreted the chemokine CCL22 at levels that effectively attracted Tregs. PegG-CSF was more efficient at enhancing the synthesis of CCL22 by CD11chighCD8α− DCs from the pancreatic lymph nodes compared with those from the spleen. Accordingly, CD11chighCD8α− DCs from the pancreatic lymph nodes of pegG-CSF recipients were more efficient than their splenic counterparts in the recruitment of Tregs upon adoptive transfer. Predictably, CD11chighCD8α− DCs failed to recruit these Tregs both in vivo and in vitro following intracellular neutralization of CCL22. These data assign a key role to CD8α− DCs and CCL22 in Treg recruitment in the protection of NOD mice against type 1 diabetes following the treatment with G-CSF.

Although chicken gonadotropin-releasing hormone (GnRH)-II is thought to occur in most animal species, its presence and that of two other variants (lamprey GnRH-III, salmon GnRH) is questionable in rodents. Here we report on the GnRH peptides present in the hypothalamus and the remaining brain of rat of both sexes during development. No immunoreactivity was detected in the elution zone of either native or hydroxylated forms of the above three variants in any of brain extracts chromatographed. The main peptides detected were mammalian GnRH (mGnRH) and m[hydroxyproline⁹]GnRH (mHypGnRH). In the hypothalamus, these peptides were associated with their free acid and precursor forms. N-terminal fragments from both native decapeptides ([1–5]GnRH) and mGnRH ([1–9]GnRH) were observed only in the hypothalamus. C-terminal fragments were detected in both tissues. The relative proportions of mGnRH and mHypGnRH showed no developmental changes in the remaining brain. The hypothalamic proportions of mHypGnRH were high on day 5, and decreased from day 15 onwards. The [Gly¹¹]-precursor to mHypGnRH molar ratio was twofold lower than with the non-hydroxylated peptides. The mGnRH to [1–9]GnRH molar ratio increased in males but decreased in females during development. No sex-related differences were observed in the native decapeptide to [1–5]GnRH molar ratio. It was concluded that (1) chicken GnRH-II is not present in all mammals, (2) mGnRH and mHypGnRH are the main GnRH isoforms present in the rat brain, (3) the processing of [Gly¹¹]-precursor into mHypGnRH occurs at a higher rate than that of mGnRH, and (4) the catabolism does not interfere with the developmental changes undergone by the mGnRH and mHypGnRH brain contents.