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Dendritic Cell Maturation and Survival Are Differentially Regulated by TNFR1 and TNFR2

Lookup NU author(s): Dr Nicola Maney, Dr Gary Reynolds, Dr Anja Krippner-Heidenreich, Professor Catharien Hilkens

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Abstract

The capacity of dendritic cells (DC) to regulate adaptive immunity is controlled by their maturation state and lifespan. Although TNF is a well-known maturation and survival factor for DC, the role of the two TNFR, TNFR1 and TNFR2, in mediating these effects is poorly understood. By using unique TNF variants that selectively signal through TNFR1 and/or TNFR2, we demonstrate differential functions of TNFR in human monocyte-derived and blood CD1c(+) DC. Activation of TNFR1, but not TNFR2, efficiently induced DC maturation, as defined by enhanced expression of cell surface maturation markers (CD83, CD86, and HLA-DR) as well as enhanced T cell stimulatory capacity. In contrast, both TNFR1 and TNFR2 significantly protected DC against cell death, indicating that innate signals can promote DC survival in the absence of DC maturation. We further show differential activation of NF-kappa B signaling pathways by the TNFR: TNFR1 activated both the p65 and p52 pathways, whereas TNFR2 triggered p52, but not p65, activation. Accordingly, the p65 NF-kappa B pathway only played a role in the prosurvival effect of TNFR1. However, cell death protection through both TNFR was mediated through the Bcl-2/Bcl-x(L) pathway. Taken together, our data show that TNFR1, but not TNFR2, signaling induces DC maturation, whereas DC survival can be mediated independently through both TNFR. These data indicate differential but partly overlapping responses through TNFR1 and TNFR2 in both inflammatory and conventional DC, and they demonstrate that DC maturation and DC survival can be regulated through independent signaling pathways.

Publication metadata

Author(s): Maney NJ, Reynolds G, Krippner-Heidenreich A, Hilkens CMU

Publication type: Article

Publication status: Published

Journal: Journal of Immunology

Year: 2014

Volume: 193

Issue: 10

Pages: 4914-4923

Print publication date: 15/11/2014

Online publication date: 06/10/2014

Acceptance date: 08/09/2014

ISSN (print): 0022-1767

ISSN (electronic): 1550-6606

Publisher: American Association of Immunologists

URL: http://dx.doi.org/10.4049/jimmunol.1302929

DOI: 10.4049/jimmunol.1302929

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