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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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IMMUNOBIOLOGY
Activin-A: a novel dendritic cell–derived cytokine that potently attenuates CD40 ligand–specific cytokine and chemokine production
Neil C. Robson1,
David J. Phillips2,
Tristan McAlpine1,
Amanda Shin1,
Suzanne Svobodova1,
Tracey Toy1,
Vinochani Pillay1,
Naomi Kirkpatrick1,
Damien Zanker1,
Kathy Wilson2,
Imke Helling1,
Heng Wei1,
Weisan Chen1,
Jonathan Cebon1, and
Eugene Maraskovsky3
1 Ludwig Institute for Cancer Research, Austin Health, Heidelberg;
2 Monash Institute of Medical Research, Monash University, Clayton; and
3 CSL Limited, Parkville, Australia
Activin-A is a transforming growth factor-β (TGF-β) superfamily member that plays a pivotal role in many developmental and reproductive processes. It is also involved in neuroprotection, apoptosis of tumor 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 (DCs) to stimulate immune responses. Human monocyte-derived DCs (MoDCs) and the CD1c+ and CD123+ peripheral 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 after exposure to bacteria, specific toll-like receptor (TLR) ligands, or CD40 ligand (CD40L). Blocking autocrine activin-A signaling in DCs using its antagonist, follistatin, enhanced DC cytokine (IL-6, IL-10, IL-12p70, and tumor necrosis factor- [TNF-]) and chemokine (IL-8, IP-10, RANTES, and MCP-1) production during CD40L stimulation, but not TLR-4 ligation. Moreover, antagonizing 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 signaling in vivo to enhance vaccine immunogenicity.
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