Mouse CD8α+ DCs and human BDCA3+ DCs are major producers of IFN-λ in response to poly IC

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the most endemic pathogens worldwide, with more than 500 million people globally currently infected with these viruses. These pathogens can cause acute and chronic hepatitis that progress to liver cirrhosis or hepatocellular carcinoma. Both viruses utilize multifaceted strategies to evade the host surveillance system and fall below the immunological radar. HBV has developed specific strategies to evade recognition by the innate immune system and is acknowledged to be a stealth virus. However, extensive research has revealed that HBV is recognized by dendritic cells (DCs) and natural killer (NK) cells. Indoleamine-2, 3-dioxygenase is an enforcer of sequential immune reactions in acute hepatitis B, and this molecule has been shown to be induced by the interaction of HBV-infected hepatocytes, DCs, and NK cells. The interleukin-28B genotype has been reported to influence HCV eradication either therapeutically or spontaneously, but the biological function of its gene product, a type-III interferon (IFN-k3), remains to be elucidated. Human BDCA3 ? DCs have also been shown to be a potent producer of IFN-k3 in HCV infection, suggesting the possibility that BDCA3 ? DCs could play a key role in developing therapeutic HCV vaccine. Here we review the current state of research on immune responses against HBV and HCV infection, with a specific focus on innate immunity. A comprehensive study based on clinical samples is urgently needed to improve our understanding of the immune mechanisms associated with viral control and thus to develop novel immune modulatory therapies to cure chronic HBV and HCV infection.

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“…Of particular interest is the report that BDCA3 ? DCs have a potent capacity to release IFN-k in response to TLR3 agonist [73].…”

Section: Subsets/bdca3 1 Dcs In Acute Hcv Infectionmentioning

confidence: 99%

Host–virus interactions in hepatitis B and hepatitis C infection

Yoshio

Kanto

2016

J Gastroenterol

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“…Homologies exist between mouse and human LT-DC subsets (4,5). Comparative transcriptomics (4)(5)(6)(7) and functional studies (7)(8)(9)(10)(11)(12) showed that human CD141 + CLEC9A + DC are homologous to mouse spleen CD8a + DC, which are specialized in cross-presentation. Mouse CD8a + DC and human CD141 + CLEC9A + DC specifically express the XCR1 chemokine receptor (4,8,9,13,14) and can therefore be coined XCR1 + DC.…”

mentioning

confidence: 99%

“…Human XCR1 + DC have been described in many tissues (6,7,15). Human and mouse XCR1 + DC specifically express high levels of TLR-3 (16) and respond to its triggering with hepatitis C virus or with the synthetic ligand polyinosinic-polycytidylic acid (PolyI:C) by IFN-l production (12,15,17) and by enhanced cross-presentation (7)(8)(9)(10)(11). The extent to which human XCR1 + DC are more efficient for cross-presentation than other human DC subsets is debated.…”

mentioning

confidence: 99%

Human XCR1+ Dendritic Cells Derived In Vitro from CD34+ Progenitors Closely Resemble Blood Dendritic Cells, Including Their Adjuvant Responsiveness, Contrary to Monocyte-Derived Dendritic Cells

Balan

Ollion

Colletti

et al. 2014

The Journal of Immunology

113

154

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Human monocyte-derived dendritic cell (MoDC) have been used in the clinic with moderately encouraging results. Mouse XCR1+ DC excel at cross-presentation, can be targeted in vivo to induce protective immunity, and share characteristics with XCR1+ human DC. Assessment of the immunoactivation potential of XCR1+ human DC is hindered by their paucity in vivo and by their lack of a well-defined in vitro counterpart. We report in this study a protocol generating both XCR1+ and XCR1− human DC in CD34+ progenitor cultures (CD34-DC). Gene expression profiling, phenotypic characterization, and functional studies demonstrated that XCR1− CD34-DC are similar to canonical MoDC, whereas XCR1+ CD34-DC resemble XCR1+ blood DC (bDC). XCR1+ DC were strongly activated by polyinosinic-polycytidylic acid but not LPS, and conversely for MoDC. XCR1+ DC and MoDC expressed strikingly different patterns of molecules involved in inflammation and in cross-talk with NK or T cells. XCR1+ CD34-DC but not MoDC efficiently cross-presented a cell-associated Ag upon stimulation by polyinosinic-polycytidylic acid or R848, likewise to what was reported for XCR1+ bDC. Hence, it is feasible to generate high numbers of bona fide XCR1+ human DC in vitro as a model to decipher the functions of XCR1+ bDC and as a potential source of XCR1+ DC for clinical use.

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“…IFN-γ cytokine in the culture medium has increased production of IFN-λ in response to poly IC and TLR ligation [29,30]. The mechanism of the anti-tumoral activity of IFN-λ produced by CD8α + DCs is not exactly identified and needs further investigations.…”

Section: Discussionmentioning

confidence: 99%

“…As shown in Figure. 1C, DCs are known to produce the IL-12p70 cytokine and to have an exceptional capacity for cross-presentation of exogenous antigens [12]. In addition, it has been reported that mouse CD8α + DCs and human equivalent BDCA3 + DCs are major producers of interferon-lambda (IFN-λ) in response to polyinosinic: polycytidylic acid (poly IC), a synthetic double-stranded RNA, and toll-like receptor (TLR) ligand [29,30]. IFN-λ has shown + DCs also to a lower extent decreased the number of these cells but the results did not reach to be significant (p=0.057).…”

Section: Animalsmentioning

confidence: 99%

Immunotherapy with tumor cell lysate-pulsed CD8α+ dendritic cells modulates intra-tumor and spleen lymphocyte subpopulations

Azadmehr

Aa²,

Amirghofran³

et al. 2013

neo

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Using cellular adjuvants including dendritic cells (DCs) has provided a promising approach in immunotherapy of cancer. Our previous study showed that mice immunization with tumor cell lysate-pulsed DCs (TL-CD8α+DCs) could significantly suppress the tumor growth and increase mice survival. The aim of the present study was to investigate the impact of TL-CD8α+DC vaccine on intra-tumor and spleen lymphocyte subpopulations in tumor-bearing mice. A Balb/c mouse model of fibrosarcoma was used and changes in various lymphocyte subpopulations including CD4 + , CD8+ and CD4T cells in mice immunized with TL-CD8α + DCs were studied. The cytotoxic activity of the lymphocytes and tumor growth inhibitory rate were also measured. Immunotherapy with TL-CD8α + DCs significantly enhanced both CD4+ and CD8+ lymphocytes, whereas decreased CD4 + CD25 + Foxp3 + regulatory T cells as well as the tumor growth rate. There was also a decrease in the ratio of regulatory T cells to CD4 + and to CD8 + lymphocytes in both the tumor and spleen tissues as compared to that in the non-immunized control mice. Immunization with TL-CD8α + DCs as well as CD8α + DCs significantly increased the splenocytes cytotoxic activity by 45.1% and 18.2% of control, respectively. In conclusion, the current study indicated that TL-CD8α + DCs can enhance tumor immunity against the fibrosarcoma by enhancing both the CD4 + and CD8 + lymphocytes and reducing regulatory T cells. This finding suggests the usefulness of TL-CD8α + DCs vaccine for cancer treatment.

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Mouse CD8α+ DCs and human BDCA3+ DCs are major producers of IFN-λ in response to poly IC

Abstract: In humans and mice, CD8α+ conventional dendritic cells are the primary source of interferon-λ released in response to the adjuvant and Toll-like receptor 3 agonist poly IC.

Cited by 247 publications

References 83 publications

Host–virus interactions in hepatitis B and hepatitis C infection

Host–virus interactions in hepatitis B and hepatitis C infection

Human XCR1+ Dendritic Cells Derived In Vitro from CD34+ Progenitors Closely Resemble Blood Dendritic Cells, Including Their Adjuvant Responsiveness, Contrary to Monocyte-Derived Dendritic Cells

Immunotherapy with tumor cell lysate-pulsed CD8α+ dendritic cells modulates intra-tumor and spleen lymphocyte subpopulations

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