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* Cancer Immunology Research Program, Peter MacCallum Cancer Centre, Melbourne, Australia;
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia;
The Netherlands Cancer Institute, Amsterdam, The Netherlands; and
Department of Pathology, University of Melbourne, Australia
To gain ample numbers of dendritic cells (DCs) for investigation, or for immunotherapy, the culture of DC precursors from bone marrow in either GM-CSF and IL-4 (GM/IL4-DCs) or Flt3L (FL-DCs) has often been used. Despite their common use, the relationship of these culture-derived DCs to those in vivo, and their relative potential for use in immunotherapy, needs further elucidation. In this study we found that in contrast to FL-DCs, highly purified GM/IL4-DCs were larger and more granular, surface Mac-3+, and were comprised of two populations (CD24lowCD11bhigh and CD24highCD11blow). Functionally, although comparable in T cell activation, GM/IL4-DCs produced more inflammatory mediators including TNF-
, IL-10, CCL-2, and NO than FL-DCs upon TLR ligation. However, FL-DCs migrated more efficiently to draining lymph nodes after s.c. injection and produced a different profile of cytokines to GM/IL4-DCs. Developmentally, unlike GM/IL4-DCs, FL-DCs cannot be differentiated from CD11bhighLy6ChighLy6G– monocytes. Collectively, these data suggest that the GM/IL4-DCs are the equivalents of the TNF- and inducible NO synthase producing DCs in vivo that emerge after inflammation whereas FL-DCs better represent the steady-state resident DCs. The differences between GM/IL4-DCs and FL-DCs have serious implications for DC-based immunotherapeutic strategies.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Health and Medical Research Council of Australia (NH&MRC) and Juvenile Diabetes Research Foundation. Y.X. is supported by Peter Doherty Fellowship from NH&MRC 400426. S.H.N. was funded under NH&MRC (Program Grant number: 215203) but now is a Marie Curie Fellow funded by the European Union. Y.Z. is supported by RD Wright Fellowship from NH&MRC. A.M.L. is supported by Juvenile Diabetes Research Foundation and NH&MRC. M.H.K. is supported by fellowships from NH&MRC and National Breast Cancer Foundation of Australia.
2 Address correspondence and reprint requests to Dr. Yuekang Xu or Dr. Michael H. Kershaw, Cancer Immunology Research Program, Peter MacCallum Cancer Centre, St. Andrews Place, Melbourne, Victoria, 3002 Australia. E-mail addresses: yuekang.xu{at}petermac.org or michael.kershaw{at}petermac.org
3 Abbreviations used in this paper: DC, dendritic cell; cDC, conventional DC; pre-DC, precursors of DC; pDC, plasmacytoid DC; Tip-DC, TNF- and inducible NO synthase-producing DCs; BM, bone marrow; Flt3L, fms-like tyrosine kinase 3 ligand; GM/IL4-DC, DC derived from GM-CSF/IL-4 culture; FL-DC, DC derived from Flt3L culture.
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