Capacity Of Plasmacytoid Dendritic Cells Research Articles

Regulatory T cells and immunoglobulin E: A new therapeutic link for autoimmunity?

Autoimmune diseases have a prevalence of approximately 7 to 9% and are classified as either organ-specific diseases, including type I diabetes, multiple sclerosis, inflammatory bowel disease and myasthenia gravis, or systemic diseases, including systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome. While many advancements have been made in understanding of the mechanisms of autoimmune disease, including the nature of self-tolerance and its breakdown, there remain unmet needs in terms of effective and highly targeted treatments. T regulatory cells (Tregs) are key mediators of peripheral tolerance and are implicated in many autoimmune diseases, either as a result of reduced numbers or altered function. Tregs may be broadly divided into those generated in the thymus (tTregs) and those generated in the periphery (pTregs). Tregs target many different immune cell subsets and tissues to suppress excessive inflammation and to support tissue repair and homeostasis: there is a fine balance between Treg cell stability and the plasticity that is required to adjust Tregs' regulatory purposes to particular immune responses. The central role of immunoglobulin E (IgE) in allergic disease is well recognized, and it is becoming increasingly apparent that this immunoglobulin also has a wider role encompassing other diseases including autoimmune disease. Anti-IgE treatment restores the capacity of plasmacytoid dendritic cells (pDCs) impaired by IgE- high-affinity IgE receptor (FcεR1) cross-linking to induce Tregs in vitro in atopic patients. The finding that anti-IgE therapy restores Treg cell homeostasis, and that this mechanism is associated with clinical improvement in asthma and chronic spontaneous urticaria suggests that anti-IgE therapy may also have a potential role in the treatment of autoimmune diseases in which Tregs are involved.

Genome-wide analysis of TNF-alpha response in pigs challenged with porcine circovirus 2b.

Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine with a role in activating adaptive immunity to viral infections. By inhibiting the capacity of plasmacytoid dendritic cells to produce interferon-α and TNF-α, porcine circovirus 2 (PCV2) limits the maturation of myeloid dendritic cells and impairs their ability to recognize viral and bacterial antigens. Previously, we reported QTL for viremia and immune response in PCV2-infected pigs. In this study, we analyzed phenotypic and genetic relationships between TNF-α protein levels, a potential indicator of predisposition to PCV2 co-infection, and PCV2 susceptibility. Following experimental challenge with PCV2b, TNF-α reached the peak at 21 days post-infection (dpi), at which time a difference was observed between pigs that expressed extreme variation in viremia and growth (P < 0.10). A genome-wide association study (n = 297) revealed that genotypes of 56,433 SNPs explained 73.9% of the variation in TNF-α at 21 dpi. Major SNPs were identified on SSC8, SSC10 and SSC14. Haplotypes based on SNPs from a SSC8 (9 Mb) 1-Mb window were associated with variation in TNF-α (P < 0.02), IgG (P = 0.05) and IgM (P < 0.13) levels at 21 dpi. Potential overlap of regulatory mechanisms was supported by the correlations between genomic prediction values of TNF-α and PCV2 antibodies (21 dpi, r > 0.22), viremia (14-21 dpi, P > 0.29) and viral load (r = 0.31, P < 0.0001). Characterization of the QTL regions uncovered genes that could influence variation in TNF-α levels as well as T- and B-cell development, which can affect disease susceptibility.

Modulation of Type I Interferon-Associated Viral Sensing during Acute Simian Immunodeficiency Virus Infection in African Green Monkeys

Natural hosts of simian immunodeficiency virus (SIV), such as African green monkeys (AGMs), do not progress to AIDS when infected with SIV. This is associated with an absence of a chronic type I interferon (IFN-I) signature. It is unclear how the IFN-I response is downmodulated in AGMs. We longitudinally assessed the capacity of AGM blood cells to produce IFN-I in response to SIV and herpes simplex virus (HSV) infection. Phenotypes and functions of plasmacytoid dendritic cells (pDCs) and other mononuclear blood cells were assessed by flow cytometry, and expression of viral sensors was measured by reverse transcription-PCR. pDCs displayed low BDCA-2, CD40, and HLA-DR expression levels during AGM acute SIV (SIVagm) infection. BDCA-2 was required for sensing of SIV, but not of HSV, by pDCs. In acute infection, AGM peripheral blood mononuclear cells (PBMCs) produced less IFN-I upon SIV stimulation. In the chronic phase, the production was normal, confirming that the lack of chronic inflammation is not due to a sensing defect of pDCs. In contrast to stimulation by SIV, more IFN-I was produced upon HSV stimulation of PBMCs isolated during acute infection, while the frequency of AGM pDCs producing IFN-I upon in vitro stimulation with HSV was diminished. Indeed, other cells started producing IFN-I. This increased viral sensing by non-pDCs was associated with an upregulation of Toll-like receptor 3 and IFN-γ-inducible protein 16 caused by IFN-I in acute SIVagm infection. Our results suggest that, as in pathogenic SIVmac infection, SIVagm infection mobilizes bone marrow precursor pDCs. Moreover, we show that SIV infection modifies the capacity of viral sensing in cells other than pDCs, which could drive IFN-I production in specific settings. The effects of HIV/SIV infections on the capacity of plasmacytoid dendritic cells (pDCs) to produce IFN-I in vivo are still incompletely defined. As IFN-I can restrict viral replication, contribute to inflammation, and influence immune responses, alteration of this capacity could impact the viral reservoir size. We observed that even in nonpathogenic SIV infection, the frequency of pDCs capable of efficiently sensing SIV and producing IFN-I was reduced during acute infection. We discovered that, concomitantly, cells other than pDCs had increased abilities for viral sensing. Our results suggest that pDC-produced IFN-I upregulates viral sensors in bystander cells, the latter gaining the capacity to produce IFN-I. These results indicate that in certain settings, cells other than pDCs can drive IFN-I-associated inflammation in SIV infection. This has important implications for the understanding of persistent inflammation and the establishment of viral reservoirs.

Diminished IL-12 production mediates impaired T-cell stimulating capacity of lymph node dendritic cells and macrophages in SIV infection (INC9P.444)

Abstract Mononuclear phagocytes are integral components of the innate immune system that sense invading microbes and expand antigen-specific immune responses. Thus far, their roles in progressive HIV infection remain to be clarified. We used the pathogenic simian immunodeficiency virus (SIV) rhesus macaque model to determine the immune stimulating capacity of plasmacytoid dendritic cells (pDC), myeloid DC (mDC), and macrophages (Mφ) after SIV infection, focusing on the lymph node compartment. By positive selection through live-cell sorting, we measured the ex vivo ability of each subset to respond to uridine-rich ssRNA oligos derived from the infecting strain of SIV and to subsequently drive CD4+ T cell proliferation and IFN-γ production. Isolated pDC and Mφ from infected macaques were defective at stimulating CD4+ T cells to divide and produce IFN-γ. Co-stimulatory marker upregulation on mononuclear phagocytes remained comparable in naïve and infected samples, whereas deficiencies in IFN-α and IL-12 production by pDC and Mφ were found concurrent with lower CD4+ T cell function. Furthermore, exogenous IFN-α and IL-12 supplementation was able to recover the CD4+ T cell stimulating capacity of isolated mDC and Mφ from SIV-infected lymphatic tissue. These novel findings suggest that defects in mononuclear phagocyte T cell stimulating capacity through loss of IL-12 production may contribute to the overall immune dysfunction in pathogenic SIV of rhesus macaques and HIV infection of humans.

Persistent Virus Infection Inhibits Type I Interferon Production by Plasmacytoid Dendritic Cells to Facilitate Opportunistic Infections

Emerging studies indicate an association between virus-induced impairment in type I interferon (IFN-I) production and enhanced susceptibility to opportunistic infections, which represent a major health problem. Here, we provide in vivo evidence that lymphocytic choriomeningitis virus (LCMV) infection of its natural murine host dramatically diminishes the unique capacity of plasmacytoid dendritic cells (pDCs) to secrete high levels of systemic IFN-I. While both acute and persistent LCMV infections suppress pDC IFN-I response, only the persistent virus induces a long-lasting diversion of this innate immune pathway. The consequent reduction in IFN-I production serves to impair natural killer cell responses in LCMV-infected mice challenged subsequently with murine cytomegalovirus (MCMV) as an opportunistic pathogen. This innate defect also compromises the host's ability to counteract early MCMV spread. These findings provide a mechanistic explanation for the occurrence of opportunistic infections following viral insults and have important implications for treating such medical complications.

Papillomavirus virus‐like particles induce cytokines characteristic of innate immune responses in plasmacytoid dendritic cells

Human papillomavirus (HPV) virus-like particles (VLP) are being extensively tested as vaccines for the prevention of HPV-associated cervical cancer. Dendritic cells (DC) acquire and present antigens, initiating innate and adaptive immune responses. It has been shown previously that DC of the myeloid lineage are capable of generating adaptive immune responses to HPV VLP in vitro. However, the capacity of plasmacytoid DC (pDC) to acquire HPV VLP and the nature of the immune response generated have not been reported. In this study we found that freshly isolated as well as CpG-matured pDC bind papillomavirus VLP and that internalization occurs preferentially in the immature pDC. In contrast to myeloid DC, pDC did not undergo phenotypic maturation upon exposure to HPV16 VLP. However, HPV16 VLP induced pDC to secrete of IFN-alpha and IL-6, both cytokines that play a role in the generation of antibody responses, as well as TNFalpha and IL-8. Given that VLP do not contain viral nucleic acids, these results indicate that viral capsids alone may be capable of inducing cytokine production by pDC. Finally, CpG-activated pDC, but not pDC exposed to HPV16 VLP, activated lymphocytes to secrete IL-10 and low levels of IFN-gamma. Together these findings suggest a possible immunogenic effect of pDC in the setting of VLP vaccination.