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"Alternatively Activated" Dendritic Cells Preferentially Secrete IL-10, Expand Foxp3⁺CD4⁺ T Cells, and Induce Long-Term Organ Allograft Survival in Combination with CTLA4-Ig¹

Yuk Yuen Lan^*,, Zhiliang Wang^*, Giorgio Raimondi^*, Wenhan Wu^*, Bridget L. Colvin^*, An De Creus^* and Angus W. Thomson^2,*,

^* Thomas E. Starzl Transplantation Institute and Department of Surgery and Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213

In this study, we propagated myeloid dendritic cells (DC) from BALB/c (H2^d) mouse bone marrow progenitors in IL-10 and TGF-, then stimulated the cells with LPS. These "alternatively activated" (AA) DC expressed lower TLR4 transcripts than LPS-stimulated control DC and were resistant to maturation. They expressed comparatively low levels of surface MHC class II, CD40, CD80, CD86, and programmed death-ligand 2 (B7-DC; CD273), whereas programmed death-ligand 1 (B7-H1; CD274) and inducible costimulatory ligand expression were unaffected. AADC secreted much higher levels of IL-10, but lower levels of IL-12p70 compared with activated control DC. Their poor allogeneic (C57BL/10; B10) T cell stimulatory activity and ability to induce alloantigen-specific, hyporesponsive T cell proliferation was not associated with enhanced T cell apoptosis. Increased IL-10 production was induced in the alloreactive T cell population, wherein CD4⁺Foxp3⁺ cells were expanded. The AADC-expanded allogeneic CD4⁺CD25⁺ T cells showed enhanced suppressive activity for T cell proliferative responses compared with freshly isolated T regulatory cells. In vivo migration of AADC to secondary lymphoid tissue was not impaired. A single infusion of BALB/c AADC to quiescent B10 recipients induced alloantigen-specific hyporesponsive T cell proliferation and prolonged subsequent heart graft survival. This effect was potentiated markedly by CTLA4-Ig, administered 1 day after the AADC. Transfer of CD4⁺ T cells from recipients of long-surviving grafts (>100 days) that were infiltrated with CD4⁺Foxp3⁺ cells, prolonged the survival of donor-strain hearts in naive recipients. These data enhance insight into the regulatory properties of AADC and demonstrate their therapeutic potential in vascularized organ 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 This work was supported by National Institutes of Health Grants R01 DK49745, R01 AI41011, and R01 AI60994 (to A.W.T.) and by an American Heart Association Predoctoral Fellowship (515403U) (to Y.Y.L.). B.L.C. is the recipient of an American Society of Transplantation Basic Science Fellowship and G.R. is in receipt of a Research Training Fellowship from the Transplantation Society.

² Address correspondence and reprint requests to Dr. Angus W. Thomson, University of Pittsburgh, W1544 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213. E-mail address: thomsonaw{at}msx.upmc.edu

³ Abbreviations used in this paper: DC, dendritic cell; BM, bone marrow; Treg, regulatory T cell; GVHD, graft-versus-host disease; AADC, alternatively activated DC; Foxp3, Forkhead winged helix protein-3; CM, complete medium; PD-L1, programmed death-ligand 1; MFI, mean fluorescence intensity; PI, propidium iodide; MHC II, MHC class II.

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