Human Liver Dendritic Cells Promote T Cell Hyporesponsiveness

Bamboat, Zubin M.; Stableford, Jennifer; Plitas, George; Burt, Bryan M.; Nguyen, Hoang Minh; Welles, Alexander P.; Gönen, Mithat; Young, James W.; DeMatteo, Ronald P.

doi:10.4049/jimmunol.0803404

Cited by 187 publications

(195 citation statements)

References 48 publications

Supporting

Mentioning

172

Contrasting

Order By: Relevance

“…Tissue-resident DCs may undergo local conditioning and adapt their function to the surrounding environment. This notion is supported by data on the unique regulatory mechanisms exhibited by intestinal DCs (60) and our prior work highlighting functional differences between freshly isolated human liver and autologous blood DCs (18). Another limitation of our study is that cDC depletion in the CD11c-DTR mouse is not confined to the liver.…”

Section: Figuresupporting

confidence: 51%

“…Hepatic DCs have been shown to exhibit tolerogenic properties and are thought to protect the liver from untoward inflammatory responses to foreign antigens entering the portal circulation (17). We recently discovered that freshly isolated human liver DCs exhibit a propensity for IL-10 secretion at baseline and after TLR stimulation (18). Because TLR9 has been implicated as an important regulator of inflammation through its detection of both bacterial and host DNA (19,20), we sought to determine whether TLR9 activation and cDC production of IL-10 were necessary to confer protection against liver I/R injury.…”

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion

Bamboat¹,

Ocuin²,

et al. 2010

Self Cite

View full text Add to dashboard Cite

TLRs are recognized as promoters of tissue damage, even in the absence of pathogens. TLR binding to damage-associated molecular patterns (DAMPs) released by injured host cells unleashes an inflammatory cascade that amplifies tissue destruction. However, whether TLRs possess the reciprocal ability to curtail the extent of sterile inflammation is uncertain. Here, we investigated this possibility in mice by studying the role of conventional DCs (cDCs) in liver ischemia/reperfusion (I/R) injury, a model of sterile inflammation. Targeted depletion of mouse cDCs increased liver injury after I/R, as assessed by serum alanine aminotransferase and histologic analysis. In vitro, we identified hepatocyte DNA as an endogenous ligand to TLR9 that promoted cDCs to secrete IL-10. In vivo, cDC production of IL-10 required TLR9 and reduced liver injury. In addition, we found that inflammatory monocytes recruited to the liver via chemokine receptor 2 were downstream targets of cDC IL-10. IL-10 from cDCs reduced production of TNF, IL-6, and ROS by inflammatory monocytes. Our results implicate inflammatory monocytes as mediators of liver I/R injury and reveal that cDCs respond to DAMPS during sterile inflammation, providing the host with protection from progressive tissue damage.

show abstract

Section: Figuresupporting

confidence: 51%

Section: Figurementioning

confidence: 99%

Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion

Bamboat¹,

Ocuin²,

et al. 2010

Self Cite

View full text Add to dashboard Cite

show abstract

“…The relevance of these findings to cirrhosis in humans is important. A recent report found that human liver DCs are composed primarily of BDCA-1 and BDCA-3 subsets and, similar to their murine counterparts, induce tolerogenic T cells responses to antigen and the expansion of Tregs (14). Further work is required in order to characterize the changes in human liver DCs in cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-α

Connolly¹,

Bedrosian²,

Clair³

et al. 2009

J. Clin. Invest.

184

201

View full text Add to dashboard Cite

Hepatic fibrosis occurs during most chronic liver diseases and is driven by inflammatory responses to injured tissue. Because DCs are central to modulating liver immunity, we postulated that altered DC function contributes to immunologic changes in hepatic fibrosis and affects the pathologic inflammatory milieu within the fibrotic liver. Using mouse models, we determined the contribution of DCs to altered hepatic immunity in fibrosis and investigated the role of DCs in modulating the inflammatory environment within the fibrotic liver. We found that DC depletion completely abrogated the elevated levels of many inflammatory mediators that are produced in the fibrotic liver. DCs represented approximately 25% of the fibrotic hepatic leukocytes and showed an elevated CD11b + CD8 -fraction, a lower B220 + plasmacytoid fraction, and increased expression of MHC II and CD40. Moreover, after liver injury, DCs gained a marked capacity to induce hepatic stellate cells, NK cells, and T cells to mediate inflammation, proliferation, and production of potent immune responses. The proinflammatory and immunogenic effects of fibrotic DCs were contingent on their production of TNF-α. Therefore, modulating DC function may be an attractive approach to experimental therapeutics in fibro-inflammatory liver disease.

show abstract

“…56,57 The little information that is known about human intrahepatic DC function corroborates these general observations. 58,59 Despite the challenges of accessing specimens and extracting cells, a better understanding of how DCs and monocytes function in the intrahepatic environment is important for therapeutic development.…”

Section: Areas Of Further Investigationmentioning

confidence: 99%

Dissecting the dendritic cell controversy in chronic hepatitis B virus infection

Gehring

D’Angelo

2014

Cell Mol Immunol

View full text Add to dashboard Cite

Therapeutic vaccines to boost endogenous T-cell immunity rely on the stimulatory capacity of dendritic cells (DCs). The functionality of DCs in chronic hepatitis B virus (HBV) infection has been a long-standing debate. Therefore, we have attempted to summarize multiple studies investigating DC function in chronic HBV patients to determine whether common observations can be drawn. We found that the frequency and function of ex vivo-tested myeloid and plasmacytoid DCs were largely intact in patients with HBV infection and similar to those of healthy donor DCs. The main exception was reduced IFN-a production by plasmacytoid DC from chronic HBV patients. This reduced IFN-a production correlated with liver inflammation in multiple studies but not with viral load, suggesting that viral antigens have little effect on DC function. The majority of the confusion about DC function arises from studies reporting the reduced function of healthy donor DCs exposed to various sources of HBV in vitro. These direct effects of viral antigens are in contrast to data from HBV-infected patients. The variations in the assays used and areas that require further investigation are also covered

show abstract

Human Liver Dendritic Cells Promote T Cell Hyporesponsiveness

Cited by 187 publications

References 48 publications

Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion

Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion

In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-α

Dissecting the dendritic cell controversy in chronic hepatitis B virus infection

Contact Info

Product

Resources

About