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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2733-2743.
Prepublished online as a Blood First Edition Paper on December 21, 2007; DOI 10.1182/blood-2007-03-080994.
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Submitted March 21, 2007
Accepted November 29, 2007
Activin-A: a novel dendritic cell derived cytokine which potently attenuates CD40 ligand-specific cytokine and chemokine production
Neil C Robson*, David J Phillips, Tristan McAlpine, Amanda Shin, Suzanne Svobodova, Tracey Toy, Vinochani Pillay, Naomi Kirkpatrick, Damien Zanker, Kathy Wilson, Imke Helling, Heng Wei, Weisan Chen, Jonthan Cebon, and Eugene Maraskovsky
Melbourne Centre for Clinical Sciences, Ludwig Institute for Cancer Research, Austin Health, Heidelberg, VIC, Australia
Centre for Reproduction and Development, Monash Institute of Medical Research, Monash University, Clayton, VIC, Australia
Research Department, CSL Limited, Parkville, VIC, Australia
* Corresponding author; email: neil.robson{at}ludwig.edu.au.
Activin-A is a transforming growth factor- (TGF-) superfamily member which plays a pivotal role in many developmental and reproductive processes. It is also involved in neuroprotection, apoptosis of tumour and some immune cells, wound healing and cancer. Its role as an immune regulating protein has not previously been described. Here we demonstrate for the first time that activin-A has potent autocrine effects on the capacity of human dendritic cells to stimulate immune responses. Human monocyte-derived DCs (MoDCs) and the CD1c+ and CD123+ blood DC populations express both activin-A and the type I and II activin receptors. Furthermore, MoDCs and CD1c+ myeloid DCs rapidly secrete high levels of activin-A following exposure to bacteria, specific toll like receptor (TLR) ligands or CD40 ligand (CD40L). Blocking autocrine activin-A signalling in DCs using its antagonist, follistatin, enhanced DC cytokine (IL-6, IL-10, IL-12p70 and TNF- ) and chemokine (IL-8, IP-10, RANTES and MCP-1) production during CD40L stimulation, but not TLR-4 ligation. Moreover, antagonising DC derived activin-A resulted in significantly enhanced expansion of viral antigen specific effector CD8+ T cells. These findings establish an immune regulatory role for activin-A in DCs, highlighting the potential of antagonizing activin-A signalling in vivo in order to enhance vaccine immunogenicity.
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