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Blood, 2 April 2009, Vol. 113, No. 14, pp. 3218-3225.
Prepublished online as a Blood First Edition Paper on January 13, 2009; DOI 10.1182/blood-2008-07-166926.
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Submitted July 9, 2008
Accepted November 24, 2008
Activin-A attenuates several human natural killer cell functions
Neil C. Robson*, Heng Wei, Tristan McAlpine, Naomi Kirkpatrick, Jonathan Cebon, and Eugene Maraskovsky
Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences, Austin Health, Heidelberg, VIC, Australia
CSL Limited, Bio21 Institute, Parkville, VIC, Australia
* Corresponding author; email: neil.robson{at}ludwig.edu.au.
Dendritic cell (DC) - natural killer (NK) cell interactions are critical in sculpting the adaptive immune response. However, the mechanisms by which DCs down-regulate NK cell functions are not well understood. NK cell function is inhibited by transforming growth factor beta (TGF- ) but DCs do not appear to produce TGF-. We have previously shown that activated human DCs produce large amounts of activin-A, a TGF- superfamily member, which auto-regulates DC function. The present report shows that NK cells express type I and II activin receptors and activin-A triggers NK cell Smad 2/3 signalling. Furthermore, activin-A directly regulates NK cell functions by (1) down regulating the T-box transcription factor T-bet and interferon gamma (IFN- ), but not perforin or granzyme mRNA; (2) suppressing NK cell IFN- production as potently as TGF-; and (3) suppressing NK cell CD25 expression and proliferation and sculpting NK cell cytokine and chemokine profiles. Interestingly, unlike TGF-, activin-A weakly down regulates the NK cell natural cytotoxicity receptors (NCRs) NKp30 and NKG2D but does not attenuate their cytotoxic function. These findings provide the first evidence for a novel immune regulatory role of activin-A during DC-mediated NK cell regulation, highlighting the potential of antagonizing activin-A signalling in vivo in order to enhance NK cell-mediated immune functions and adaptive immunity.
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M. Semitekolou, T. Alissafi, M. Aggelakopoulou, E. Kourepini, H. H. Kariyawasam, A. B. Kay, D. S. Robinson, C. M. Lloyd, V. Panoutsakopoulou, and G. Xanthou
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