Critical Role for TNF in the Induction of Human Antigen-Specific Regulatory T Cells by Tolerogenic Dendritic Cells

Kleijwegt, Fleur S.; Laban, Sandra; Duinkerken, Gaby; Joosten, Antoinette M.; Zaldumbide, Arnaud; Nikolić, Tatjana; Roep, Bart O.

doi:10.4049/jimmunol.1000560

Cited by 118 publications

(101 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In T cells, 1,25[OH] 2 D has been reported to prime T-cell receptor mediated cellular activation [24] but in different experimental models, to attenuate Th1-type responses and promote regulatory T-cell development [13,[25][26][27][28][29] potentially by direct induction of the FoxP3 transcription factor [30]. In macrophages, 1,25[OH] 2 D enhances host restriction of intracellular pathogens.…”

Section: Discussionmentioning

confidence: 99%

Regulation of CYP27B1 and CYP24A1 hydroxylases limits cell‐autonomous activation of vitamin D in dendritic cells

et al. 2014

View full text Add to dashboard Cite

Keywords: CYP27B1 r CYP24A1 r DCs r Macrophages r Vitamin D Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe capacity of vitamin D metabolites to modulate macrophage and DC function has been subject to extensive research interest in light of the association of vitamin D deficiency with a broad spectrum of immunological and infectious diseases. This gives Correspondence: Dr. Mahdad Noursadeghi e-mail: m.noursadeghi@ucl.ac.uk way to the potential for vitamin D supplementation [1][2][3][4] or ex vivo conditioning of DCs with vitamin D for cell therapy strategies [5]. Vitamin D is synthesized from 7-dehydrocholesterol in the skin following exposure to ultraviolet B radiation and thermal isomerisation, or replenished by dietary intake. It is 25-hydroxylated in the liver to form 25-hydroxyvitamin D (25[OH]D), which is in * These authors contributed equally to this work. Results 25[OH]D is not functionally activated during monocyte differentiation to immature DCsWe first compared the activation of 25[OH]D during monocyte differentiation into macrophages and immature DCs. Conventional cell culture media in this model are vitamin D deficient (Fig. 1A) (Fig. 1B). This was also associated with upregulation of the prototypic vitamin D-inducible gene cathelicidin (CAMP) in macrophages (Fig. 1C) (Fig. 1C). Importantly, upregulation of DC-SIGN during monocyte differentiation to DCs was not affected by the presence of 1,25[OH] 2 D (Fig. 1D) DCs show time-dependent increase in activation of 25[OH]D independent of CYP27B1 expression levelsWe confirmed previous observations [16] that expression of the vitamin D-activating hydroxylase CYP27B1 is significantly lower in DCs compared with MDMs at both transcript and protein levels ( Fig. 2A and B). In contrast, vitamin D receptor (VDR) expression was higher in DCs than MDMs ( Fig. 2A). Taken together, these data further support the hypothesis that 25[OH]D has no effect on DCs in the experiments described above, because of a failure to generate 1,25[OH] 2 D rather than an inability to respond to 1,25[OH] 2 D. We also confirmed that 24-h stimulation of DCs with LPS significantly increases transcript and protein levels of CYP27B1 ( Fig. 2B and C (Fig. 2D). However, there was no concomitant upregulation of CAMP (Fig. 2C) . Monocytes are typically differentiated to DCs over 4-7 days, therefore we considered the possibility that time in culture may confound comparisons between different studies. Interestingly, we did find 25[OH]D-dependent upregulation of CAMP gene expression in DCs that increased with time after at least 6 days in culture (Fig. 2E). This was not associated with any significant time-dependent increase in CYP27B1 expression ( DCs express truncated CYP27B1 transcriptsWe found that LPS stimulation was able to upregulate DC expression of CYP27B1 transcript to levels higher than that in MDMs ( Figs. 2A and C). However, the expression of CYP27B1 protein remains much lower in DCs compared with ...

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation of CYP27B1 and CYP24A1 hydroxylases limits cell‐autonomous activation of vitamin D in dendritic cells

et al. 2014

View full text Add to dashboard Cite

show abstract

“…47,48 Likewise, controlled induction of IL-10 or TNF in diabetes could improve wound healing or the regulation of the autoimmune response. 49,50 …”

Section: Discussionmentioning

confidence: 99%

The DNA-binding factor Ctcf critically controls gene expression in macrophages

et al. 2013

Self Cite

View full text Add to dashboard Cite

“…More recently, a role for TNFR2 signaling in the selective killing of autoreactive T cells (4) and the promotion of regulatory T-cell function and expansion (14) have been demonstrated. In line with this, tolerogenic roles of mTNF could also be attributed to TNFR2 (1,34). Indeed, the importance of differential signaling via TNFR1 and TNFR2 in balancing specific immune responses provides a potential target to improve anti-TNF therapies (11,14,20,36) and requires a more detailed understanding of the differential responsiveness of the two TNFRs to sTNF.…”

mentioning

confidence: 87%

The Tumor Necrosis Factor Receptor Stalk Regions Define Responsiveness to Soluble versus Membrane-Bound Ligand

Richter

Messerschmidt

Holeiter

et al. 2012

Molecular and Cellular Biology

View full text Add to dashboard Cite

The family of tumor necrosis factor receptors (TNFRs) and their ligands form a regulatory signaling network that controls immune responses. Various members of this receptor family respond differently to the soluble and membrane-bound forms of their respective ligands. However, the determining factors and underlying molecular mechanisms of this diversity are not yet understood. Using an established system of chimeric TNFRs and novel ligand variants mimicking the bioactivity of membranebound TNF (mTNF), we demonstrate that the membrane-proximal extracellular stalk regions of TNFR1 and TNFR2 are crucial in controlling responsiveness to soluble TNF (sTNF). We show that the stalk region of TNFR2, in contrast to the corresponding part of TNFR1, efficiently inhibits both the receptor's enrichment/clustering in particular cell membrane regions and ligandindependent homotypic receptor preassembly, thereby preventing sTNF-induced, but not mTNF-induced, signaling. Thus, the stalk regions of the two TNFRs not only have implications for additional TNFR family members, but also provide potential targets for therapeutic intervention.

show abstract

Critical Role for TNF in the Induction of Human Antigen-Specific Regulatory T Cells by Tolerogenic Dendritic Cells

Abstract: Material

Cited by 118 publications

References 35 publications

Regulation of CYP27B1 and CYP24A1 hydroxylases limits cell‐autonomous activation of vitamin D in dendritic cells

Regulation of CYP27B1 and CYP24A1 hydroxylases limits cell‐autonomous activation of vitamin D in dendritic cells

The DNA-binding factor Ctcf critically controls gene expression in macrophages

The Tumor Necrosis Factor Receptor Stalk Regions Define Responsiveness to Soluble versus Membrane-Bound Ligand

Contact Info

Product

Resources

About