Plasmacytoid dendritic cells accumulate in spleens from chronically HIV-infected patients but barely participate in interferon- expression

Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, Paris, France.
Blood (Impact Factor: 10.45). 05/2009; 113(24):6112-9. DOI: 10.1182/blood-2008-07-170803
Source: PubMed

ABSTRACT We characterized the localization, phenotype, and some functions of plasmacytoid dendritic cells (pDCs) in the human spleen. pDCs were localized in the marginal zone and the periarteriolar region. Some were also found in the red pulp. pDCs were immature by phenotypic labeling, consistently with their capacity to internalize Dextran in a functional assay. In spleens from HIV-infected patients with thrombocytopenic purpura, these characteristics were unaffected. However, an accumulation of pDCs, but not myeloid dendritic cells (mDCs), was observed in some HIV+ patients, correlating with high proviral loads. Moreover, although undetectable in most HIV- patients, interferon-alpha (IFN-alpha) production was evidenced in situ and by flow cytometry in most HIV+ patients. IFN-alpha was located in the marginal zone. Surprisingly, IFN-alpha colocalized only with few pDCs, but rather with other cells, including T and B lymphocytes, mDCs, and macrophages. Therefore, pDCs accumulated in spleens from HIV+ patients with high proviral loads, but they did not seem to be the main IFN-alpha producers.

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    • "This diminution may be consequence of decreased numbers of circulating pDCs [13], [14], decreased IFN-I production by pDCs, or a combination of both [15], [16], implying that cells other than peripheral blood pDCs are sources for elevated IFN-I levels. Others have suggested that splenic T and B cells may be a source for IFN-I [17]. Uncertainty regarding both the identity and source of elevated IFN-I has limited understanding of the drivers of its expression. "
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    ABSTRACT: Type-I interferon (IFN-I) has been increasingly implicated in HIV-1 pathogenesis. Various studies have shown elevated IFN-I and an IFN-I-induced gene and protein expression signature in HIV-1 infection, yet the elevated IFN-I species has not been conclusively identified, its source remains obscure and its role in driving HIV-1 pathogenesis is controversial. We assessed IFN-I species in plasma by ELISAs and bioassay, and we investigated potential sources of IFN-I in blood and lymph node tissue by qRT-PCR. Furthermore, we measured the effect of therapeutic administration of IFNα in HCV-infected subjects to model the effect of IFNα on chronic immune activation. IFN-I bioactivity was significantly increased in plasma of untreated HIV-1-infected subjects relative to uninfected subjects (p = 0.012), and IFNα was the predominant IFN-I subtype correlating with IFN-I bioactivity (r = 0.658, p<0.001). IFNα was not detectable in plasma of subjects receiving anti-retroviral therapy. Elevated expression of IFNα mRNA was limited to lymph node tissue cells, suggesting that peripheral blood leukocytes are not a major source of IFNα in untreated chronic HIV-1 infection. Plasma IFN-I levels correlated inversely with CD4 T cell count (p = 0.003) and positively with levels of plasma HIV-1 RNA and CD38 expression on CD8 T cells (p = 0.009). In hepatitis C virus-infected subjects, treatment with IFN-I and ribavirin increased expression of CD38 on CD8 T cells (p = 0.003). These studies identify IFNα derived from lymph nodes, rather than blood leukocytes, as a possible source of the IFN-I signature that contributes to immune activation in HIV-1 infection.
    PLoS ONE 02/2013; 8(2):e56527. DOI:10.1371/journal.pone.0056527 · 3.23 Impact Factor
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    • "Whether these macrophages may replace MZM in trapping pathogens and interacting with MZ B-cells remains to be established. In humans, CD11c+ CD205+ DCs are also intertwined with MadCAM1+ cells at the inner border of the perifollicular zone, whereas BDCA-2+ plasmacytoid DCs are present in the MZ and T-cell zones under steady-state conditions [47-50]. "
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    ABSTRACT: The immunological roles of B-cells are being revealed as increasingly complex by functions that are largely beyond their commitment to differentiate into plasma cells and produce antibodies, the key molecular protagonists of innate immunity, and also by their compartmentalisation, a more recently acknowledged property of this immune cell category. For decades, B-cells have been recognised by their expression of an immunoglobulin that serves the function of an antigen receptor, which mediates intracellular signalling assisted by companion molecules. As such, B-cells were considered simple in their functioning compared to the other major type of immune cell, the T-lymphocytes, which comprise conventional T-lymphocyte subsets with seminal roles in homeostasis and pathology, and non-conventional T-lymphocyte subsets for which increasing knowledge is accumulating. Since the discovery that the B-cell family included two distinct categories --- the non-conventional, or extrafollicular, B1 cells, that have mainly been characterised in the mouse; and the conventional, or lymph node type, B2 cells --- plus the detailed description of the main B-cell regulator, FcgammaRIIb, and the function of CD40+ antigen presenting cells as committed/memory B-cells, progress in B-cell physiology has been slower than in other areas of immunology. Cellular and molecular tools have enabled the revival of innate immunity by allowing almost all aspects of cellular immunology to be re-visited. As such, B-cells were found to express "Pathogen Recognition Receptors" such as TLRs, and use them in concert with B-cell signalling during innate and adaptive immunity. An era of B-cell phenotypic and functional analysis thus began that encompassed the study of B-cell microanatomy principally in the lymph nodes, spleen and mucosae. The novel discovery of the differential localisation of B-cells with distinct phenotypes and functions revealed the compartmentalisation of B-cells. This review thus aims to describe novel findings regarding the B-cell compartments found in the mouse as a model organism, and in human physiology and pathology. It must be emphasised that some differences are noticeable between the mouse and human systems, thus increasing the complexity of B-cell compartmentalisation. Special attention will be given to the (lymph node and spleen) marginal zones, which represent major crossroads for B-cell types and functions and a challenge for understanding better the role of B-cell specificities in innate and adaptive immunology.
    BMC Immunology 11/2012; 13(1):63. DOI:10.1186/1471-2172-13-63 · 2.48 Impact Factor
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    • "Our result showed that while wildtype (Rag2+/+) and Rag1−/− bone marrow cells produced a large amount of IFNα in response to CpG, the induction of IFNα was significantly lower in Rag2−/− bone marrow cells (Fig. 4A, left panel, p<.05; and Fig. S3), suggesting that Rag2 may be required for TLR9-mediated production of IFNα in the bone marrow. Neither Rag2+/+ nor Rag2−/− cells derived from the spleen produced a significant level of IFNα upon CpG stimulation (Fig. 4A, right panel), consistent with previous reports [35], [36]. Therefore, we focused on bone marrow cells in the following experiments. "
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    ABSTRACT: Using mice that lack recombination activating gene-2 (Rag2), we have found that bone marrow-derived plasmacytoid dendritic cells (pDCs) as main producers of interferon-α (IFNα) require Rag2 for normal development. This is a novel function for Rag2, whose classical role is to initiate B and T cell development. Here we showed that a population of common progenitor cells in the mouse bone marrow possessed the potential to become either B cells or pDCs upon appropriate stimulations, and the lack of Rag2 hindered the development of both types of progeny cells. A closer look at pDCs revealed that Rag2(-/-) pDCs expressed a high level of Ly6C and were defective at producing IFNα in response to CpG, a ligand for toll-like receptor 9. This phenotype was not shared by Rag1(-/-) pDCs. The induction of CCR7, CD40 and CD86 with CpG, however, was normal in Rag2(-/-) pDCs. In addition, Rag2(-/-) pDCs retained the function to promote antibody class switching and plasma cell formation through producing IL-6. Further analysis showed that interferon regulatory factor-8, a transcription factor important for both IFNα induction and pDC development, was dysregulated in pDCs lacking Rag2. These results indicate that the generation of interferon response in pDCs requires Rag2 and suggest the lymphoid origin of bone marrow-derived pDCs.
    PLoS ONE 10/2012; 7(10):e47952. DOI:10.1371/journal.pone.0047952 · 3.23 Impact Factor
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