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Host-Derived Langerhans Cells Persist after MHC-Matched Allografting Independent of Donor T Cells and Critically Influence the Alloresponses Mediated by Donor Lymphocyte Infusions¹

Nadira Durakovic^*, Karl B. Bezak^2,*, Mario Skarica^2,*, Vedran Radojcic^*, Ephraim J. Fuchs^*, George F. Murphy and Leo Luznik^3,*

^* Divisions of Hematologic Malignancies and Cancer Immunology and Hematopoiesis, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231; and Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115

Mouse models of minor histocompatibility Ag-mismatched bone marrow transplantation were used to study donor dendritic cell (DC) reconstitution after conditioning, variables influencing the persistence of residual host DCs in different compartments, their phenotype, and their role in governing donor lymphocyte infusion (DLI)-mediated alloresponses. Reconstitution of all splenic DC subsets occurred rapidly after bone marrow transplantation and before T cell reconstitution. However, in contrast to MHC-mismatched chimeras, residual host-derived DCs persisted in the cutaneous lymph nodes (CLNs) of MHC-matched chimeras despite the presence or addition of donor T cells to the graft. The phenotype of these residual host-derived DCs in CLNs was consistent with Langerhans’ cells (LCs). We confirmed their skin origin and found near-complete preservation of host-derived LCs in the skin. Host-derived LCs retained their ability to continuously traffic to the CLNs, expressed homogeneously increased levels of costimulatory molecules, and could capture and carry epicutaneously applied Ags. To determine the role of residual host LCs in governing DLI-mediated alloresponses, we administered DLI alone or after topical application of the TLR7 ligand imiquimod, which is known to enhance the LC emigration from the skin. DLI administration resulted in a decrease in host-derived DCs in the CLNs and increased recruitment of donor-derived DCs to the skin, whereas imiquimod augmented their alloreactivity. These results suggest uniqueness of the MHC-matched setting in relation to the persistence of host-derived DCs in the skin and points to a previously unrecognized role of host-derived LCs in the induction of DLI-mediated graft-vs-host alloresponses.

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 grant from the Amy Strelzer Manasevit Scholars Program funded by the Marrow Foundation in cooperation with the National Marrow Donor Program, National Cancer Institute (K08 CA89546, P01 CA15396, and RO1 CA40358) and the Multiple Myeloma Research Foundation.

² K.B.B. and M.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Leo Luznik, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Cancer Research Building; Room 290, 1650 Orleans Street, Baltimore, MD 21231. E-mail address: luznile{at}jhmi.edu

⁴ Abbreviations used in this paper: DC, dendritic cell; BM, bone marrow; BMT, bone marrow transplantation; alloBMT, allogeneic bone marrow transplantation; GVH, graft-vs-host; GVHD, graft-vs-host disease; miHA, minor histocompatibility Ag; LC, Langerhans cell; DLI, donor lymphocyte infusion; TBI, total body irradiation; TCD, T cell depletion; LN, lymph node; CLN, cutaneous lymph node; TRITC, tetramethylrhodamine isothiocyanate; PI, propidium iodide; Lmm, linear millimeter; epDC, epithelium-derived DC; LH-GVH, lymphohemopoietic GVH.

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