Plasmacytoid dendritic cells in HIV infection: striking a delicate balance

Fitzgerald-Bocarsly, Patricia; Jacobs, Evan

doi:10.1189/jlb.0909635

Cited by 118 publications

(117 citation statements)

References 152 publications

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“…TGF-␤ also inhibits IFN-I production by pDCs ex vivo (21) and the expression of costimulatory molecules major histocompatibility complex class II (MHC-II), CD40, and CD80/CD86 in bone marrow (BM)-derived DCs in vitro (22). Notably, DCs from mice infected with a persistent strain of LCMV, strain Cl13, have reduced maturation (23), and pDCs produce substantially reduced amounts of IFN-I compared with the amounts produced by pDCs from noninfected hosts (24), similar to the findings for pDCs from HIV-infected individuals (25). These studies raised the possibility that TGF-␤ signaling may limit DC maturation and/or cytokine production during in vivo viral infection, attenuating early viral containment and promoting viral persistence.…”

supporting

confidence: 59%

Constitutive but Not Inducible Attenuation of Transforming Growth Factor β Signaling Increases Natural Killer Cell Responses without Directly Affecting Dendritic Cells Early after Persistent Viral Infection

Lewis

Macal

Hesser

et al. 2015

J Virol

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Rapid innate responses to viral encounters are crucial to shaping the outcome of infection, from viral clearance to persistence. Transforming growth factor ␤ (TGF-␤) is a potent immune suppressor that is upregulated early upon viral infection and maintained during chronic infections in both mice and humans. However, the role of TGF-␤ signaling in regulating individual cell types in vivo is still unclear. Using infections with two different persistent viruses, murine cytomegalovirus (MCMV) and lymphocytic choriomeningitis virus (LCMV; Cl13), in their natural rodent host, we observed that TGF-␤ signaling on dendritic cells (DCs) did not dampen DC maturation or cytokine production in the early stages of chronic infection with either virus in vivo. In contrast, TGF-␤ signaling prior to (but not during) chronic viral infection directly restricted the natural killer (NK) cell number and effector function. This restriction likely compromised both the early control of and host survival upon MCMV infection but not the long-term control of LCMV infection. These data highlight the context and timing of TGF-␤ signaling on different innate cells that contribute to the early host response, which ultimately influences the outcome of chronic viral infection in vivo. IMPORTANCEIn vivo host responses to pathogens are complex processes involving the cooperation of many different immune cells migrating to specific tissues over time, but these events cannot be replicated in vitro. Viruses causing chronic infections are able to subvert this immune response and represent a human health burden. Here we used two well-characterized viruses that are able to persist in their natural mouse host to dissect the role of the suppressive molecule TGF-␤ in dampening host responses to infection in vivo. This report presents information that allows an increased understanding of long-studied TGF-␤ signaling by examining its direct effect on different immune cells that are activated very early after in vivo viral infection and may aid with the development of new antiviral therapeutic strategies.T he coordinated effort of both the innate and the adaptive immune systems is necessary to control invasive pathogens. Rapid viral dissemination has been associated with weak host antiviral responses and viral persistence in both mice and humans (1, 2). Thus, the magnitude of initial innate responses can be critical to limit the establishment of potentially chronic infections. Human chronic infections with hepatitis C virus (HCV), hepatitis B virus (HBV), human immunodeficiency virus (HIV), and Mycobacterium tuberculosis as well as mouse infections with lymphocytic choriomeningitis virus (LCMV) and the malaria parasite are associated with the increased production and/or signaling of the immunosuppressive molecule transforming growth factor ␤ (TGF-␤) in immune cells (3-7). However, the precise role of TGF-␤-mediated suppression on innate and adaptive immune components during infection has not been fully deciphered.Among innate cells, dendritic cells (DC...

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supporting

confidence: 59%

Constitutive but Not Inducible Attenuation of Transforming Growth Factor β Signaling Increases Natural Killer Cell Responses without Directly Affecting Dendritic Cells Early after Persistent Viral Infection

Lewis

Macal

Hesser

et al. 2015

J Virol

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“…Differentiation of DCs from hematopoietic progenitor cells (HPCs) is regulated by complex signaling pathways that involve soluble cytokines and transcription factors (TFs) in bone marrow (BM) and peripheral lymphoid tissues (3,4). Impaired DC differentiation facilitates the escape of tumor cells and invading pathogens from the host's immune surveillance (5)(6)(7). Although many molecular mechanisms linked to DC differentiation have been proposed, a complete picture has yet to be obtained (8)(9)(10).…”

mentioning

confidence: 99%

Cross Talk between Histone Deacetylase 4 and STAT6 in the Transcriptional Regulation of Arginase 1 during Mouse Dendritic Cell Differentiation

Yang

Wei

et al. 2015

Molecular and Cellular Biology

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c L-Arginine and L-arginine-metabolizing enzymes play important roles in the biology of some types of myeloid cells, including macrophage and myeloid-derived suppressor cells. In this study, we found evidence that arginase 1 (Arg1) is required for the differentiation of mouse dendritic cells (DCs). Expression of Arg1 was robustly induced during monocyte-derived DC differentiation. Ectopic expression of Arg1 significantly promoted monocytic DC differentiation in a granulocyte-macrophage colonystimulating factor culture system and also facilitated the differentiation of CD8␣ ؉ conventional DCs in the presence of Flt3 ligand. Knockdown of Arg1 reversed these effects. Mechanistic studies showed that the induced expression of Arg1 in differentiating DCs was caused by enhanced recruitment of histone deacetylase 4 (HDAC4) to the Arg1 promoter region, which led to a reduction in the acetylation of both the histone 3 and STAT6 proteins and subsequent transcriptional activation of Arg1. Further investigation identified a novel STAT6 binding site within the Arg1 promoter that mediated its regulation by STAT6 and HDAC4. These observations suggest that the cross talk between HDAC4 and STAT6 is an important regulatory mechanism of Arg1 transcription in DCs. Moreover, overexpression of Arg1 clearly abrogated the ability of HDAC inhibitors to suppress DC differentiation. In conclusion, we show that Arg1 is a novel regulator of myeloid DC differentiation. Dendritic cells (DCs) are specialized antigen-presenting cells that capture, process, and present antigens to T cells and thereby play important roles in both innate and adaptive immunity (1, 2). Differentiation of DCs from hematopoietic progenitor cells (HPCs) is regulated by complex signaling pathways that involve soluble cytokines and transcription factors (TFs) in bone marrow (BM) and peripheral lymphoid tissues (3, 4). Impaired DC differentiation facilitates the escape of tumor cells and invading pathogens from the host's immune surveillance (5-7). Although many molecular mechanisms linked to DC differentiation have been proposed, a complete picture has yet to be obtained (8-10).L-Arginine is a conditionally essential amino acid in adult mammals because it is required under some special circumstances such as trauma, pregnancy, and infections. L-Arginine is metabolized by arginase (Arg) to produce urea and L-ornithine and by nitric oxide synthase to produce nitric oxide and L-citrulline. There are two known Arg isoforms, Arg1 and Arg2. Arg1 is constitutively expressed in the liver, where it participates in the urea cycle, while Arg2 is located in mitochondria in various cell types (11). Recently, it was reported that Arg1 expression is induced in myeloid cells exposed to Th2 cytokines such as interleukin-4 (IL-4) and IL-13. Induction of Arg1 or Nos2 has been used to distinguish macrophages activated through either the classical or the alternative pathway (12). Upregulation of Arg1 and Nos2 is closely associated with the suppressive activity of myeloid-derived suppressor cel...

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“…46 It is probable that a delicate balance exist in vivo between the beneficial effects of IFN␣ on controlling viral load and/or coinfections (HCV and others) and detrimental side effects on immune activation, depending of viral load itself and to multiple innate factors, including pDCs. 47,48 Altogether, we have shown here that HIV disease progression correlates with the occurrence of dysfunctional naive CD8 low T cells in the setting of chronic systemic immune activation. Although the origin and the fate of these cells remain to be determined, it is tempting to extrapolate that a functionally impaired naive CD8 low T-cell compartment in vivo may further cripple T-cell immune responses during the course of HIV disease progression.…”

Section: Discussionmentioning

confidence: 97%

HIV disease progression correlates with the generation of dysfunctional naive CD8low T cells

Favre

Stoddart

Emu

et al. 2011

Blood

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Plasmacytoid dendritic cells in HIV infection: striking a delicate balance

Cited by 118 publications

References 152 publications

Constitutive but Not Inducible Attenuation of Transforming Growth Factor β Signaling Increases Natural Killer Cell Responses without Directly Affecting Dendritic Cells Early after Persistent Viral Infection

Constitutive but Not Inducible Attenuation of Transforming Growth Factor β Signaling Increases Natural Killer Cell Responses without Directly Affecting Dendritic Cells Early after Persistent Viral Infection

Cross Talk between Histone Deacetylase 4 and STAT6 in the Transcriptional Regulation of Arginase 1 during Mouse Dendritic Cell Differentiation

HIV disease progression correlates with the generation of dysfunctional naive CD8low T cells

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