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Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD 21231
Thymus-derived, naturally occurring CD4+CD25+Foxp3+ regulatory T cells (nTregs) and Tregs induced in the periphery (iTregs) have both been implicated in regulating immune responses. However, the relationship between these populations in the same host, and their relative contribution to the overall Treg pool, has not been examined. Using a tumor-induced T cell tolerance model, we find that expansion of nTregs and de novo generation of iTregs both contribute to tumor-specific T cell tolerance. In this system in which the number of tumor-specific nTregs can be controlled, the efficiency of nTreg expansion significantly exceeds that of the induction of Tregs from uncommitted progenitors in the tumor-bearing host. However, pre-existing nTregs are neither required for the induction of Tregs nor measurably impact on the extent of their accumulation. Instead, induction of Ag-specific regulatory cells from naive cells is intrinsically influenced by the tumor microenvironment and the presence of tumor Ag.
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 Grants CA96888-01 and CA15396-23 from National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Hyam I. Levitsky, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, Suite 4M51, Baltimore, MD 21231. E-mail address: hy{at}jhmi.edu
3 Abbreviations used in this paper: Treg, regulatory T cell; nTreg, naturally occurring CD4+CD25+Foxp3+ Treg; iTreg, induced Treg; GITR, glucocorticoid-induced TNFR; HA, hemagglutinin; Tg, transgenic; vacHA, vaccinia virus encoding HA; DC, dendritic cell.
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