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Department of Surgery, University of Wisconsin, Madison, WI 53792
One hallmark of acquired tolerance is bystander suppression, a process whereby Ag-specific (adaptive) T regulatory cells (TR) inhibit the T effector cell response both to specific Ag and to a colocalized third-party Ag. Using peripheral blood T cells from recipients of HLA-identical kidney transplants as responders in the trans vivo-delayed type hypersensitivity assay, we found that dendritic cells (DC), but not monocyte APCs, could mediate bystander suppression of EBV-specific recall response. When HA-1H peptide was added to mixtures of plasmacytoid DC (pDC) and T cells, bystander suppression of the response to a colocalized recall Ag occurred primarily via indolamine-2,3-dioxygenase (IDO) production. Similarly, addition of HA-1H peptide to cocultures of T cells and pDC, but not myeloid DC (mDC), induced IDO activity in vitro. When mDC presented HA-1H peptide to Ag-specific CD8+ TR, cytokine release (TGF-
, IL-10, or both) was the primary mode of bystander suppression. Bystander suppression via mDC was reversed not only by Ab to TGF- and its receptor on T cells, but also by Ab to thrombospondin-1. EBV addition did not induce IDO or thrombospondin-1 in T-DC cocultures, suggesting that these DC products are not induced by T effector cells, but only by TR cells. These results shed light upon the mechanism of bystander suppression by donor Ag-specific TR in patients with organ transplant tolerance and underscores the distinct and critical roles of mDC and pDCs in this phenomenon.
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 in part by National Institutes of Health Grant R21-AI49900-01 and by Immune Tolerance Network Grant 1814-8094 (to W.J.B.). R.A.D. was supported by the University of Wisconsin Transplant Immunology Training Grant, National Institutes of Health T32-AI052037.
2 Current address: Department of Biochemistry, University of Wisconsin, 433 Babcock Drive, Madison, WI 53792.
3 Address correspondence and reprint requests to Dr. William J. Burlingham, Division of Transplantation, G4-702 Clinical Sciences Center, 600 Highland Avenue, Madison, WI 53792. E-mail address: Burlingham{at}surgery.wisc.edu
4 Abbreviations used in this paper: TR, T regulatory cell; TE, T effector cell; TV-DTH, trans vivo-delayed type hypersensitivity; DC, dendritic cell; pDC, plasmacytoid DC; mDC, myeloid DC; IDO, indolamine-2,3-dioxygenase; 1MT, 1-methyl-tryptophan; TSP-1, thrombospondin-1; LAP, latency-associated peptide.
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