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Graft-versus-Host Disease Prevents the Maturation of Plasmacytoid Dendritic Cells¹

Tatjana Banovic^*, Kate A. Markey^*, Rachel D. Kuns^*, Stuart D. Olver^*, Neil C. Raffelt^*, Alistair L. Don^*, Mariapia A. Degli-Esposti, Christian R. Engwerda^*, Kelli P. A. MacDonald^2,* and Geoffrey R. Hill^2,3,*

^* The Queensland Institute of Medical Research Queensland, Australia; and The Lions Eye Institute, Nedlands Western Australia, Australia

The role of Ag presenting cell subsets in graft-versus-host disease (GVHD) remains unclear. We have thus examined the ability of plasmacytoid dendritic cells (pDC) to modulate transplant outcome. Surprisingly, host pDC were exquisitely sensitive to total body irradiation and were depleted before transplantation, thus allowing us to focus on donor pDC. The depletion of all pDC from bone marrow grafts resulted in an acceleration of GVHD mortality while the depletion of mature pDC from G-CSF mobilized splenic grafts had no effect. Thus, donor bone marrow pDC, but not mature pDC contained within stem cell grafts attenuate acute GVHD. In the presence of GVHD, donor pDC completely failed to reconstitute although a CD11c^low120G8⁺ precursor DC reconstituted in an exaggerated and transient manner. These cells expressed Flt-3, the macrophage colony stimulating factor receptor and, consistent with a common dendritic cell (DC) precursor, were capable of differentiation into pDC and conventional DC in vivo in the absence of GVHD. These precursors were MHC class II⁺ and CD80/86⁺ but lacked CD40, were actively presenting host Ag and inhibited GVHD and T cell proliferation in a contact-dependent fashion. These data demonstrate that GVHD prevents the maturation of pDC and instead promotes the generation of a suppressive precursor DC, further contributing to the state of immune paralysis after transplantation.

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 G.R.H. is a National Health and Medical Research Council Practitioner Fellow. K.P.A.M. is a National Health and Medical Research Council R.D. Wright Fellow. This work was supported by grants from the National Health and Medical Research Council.

T.B. designed and performed research, analyzed the data and contributed to manuscript preparation; K.A.M. designed and performed research; R.D.K. performed research; N.C.R. performed research; S. D. O. performed research; A.L.D. performed research; M.A.D.-E. contributed reagents and intellectual input; C.R.E. contributed intellectual input and experimental design; K.P.A.M. contributed intellectual input, experimental design, and performed research; and G.R.H. contributed intellectual input, experimental design, and contributed to manuscript preparation.

² K.P.M. and G.R.H. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Geoffrey Hill, Bone Marrow Transplantation Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland, Australia. E-mail address: geoffH{at}qimr.edu.au

⁴ Abbreviations used in this paper: BMT, bone marrow transplantation; GVHD, graft-versus-host disease; DC, dendritic cell; cDC, conventional DC; MLC, mixed lymphocyte culture; pre-DC, precursor DC; pDC, plasmacytoid DC; SCT, stem cell transplantation; TBI, total body irradiation.

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