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Reprogrammed FoxP3⁺ T Regulatory Cells Become IL-17⁺ Antigen-Specific Autoimmune Effectors In Vitro and In Vivo¹

Suresh Radhakrishnan^*, Rosalyn Cabrera^*, Erin L. Schenk^*, Pilar Nava-Parada^*, Michael P. Bell^*, Virginia P. Van Keulen^*, Ronald J. Marler, Sara J. Felts^* and Larry R. Pease^2,*

^* Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN 55905; and Department of Molecular Pharmacology and Experimental Therapeutics, College of Medicine, Mayo Clinic, Scottsdale, AZ 85259

Lymphocyte differentiation from naive CD4⁺ T cells into mature Th1, Th2, Th17, or T regulatory cell (Treg) phenotypes has been considered end stage in character. In this study, we demonstrate that dendritic cells (DCs) activated with a novel immune modulator B7-DC XAb (DC^XAb) can reprogram Tregs into T effector cells. Down-regulation of FoxP3 expression after either in vitro or in vivo Treg-DC^XAb interaction is Ag-specific, IL-6-dependent, and results in the functional reprogramming of the mature T cell phenotype. The reprogrammed Tregs cease to express IL-10 and TGFβ, fail to suppress T cell responses, and gain the ability to produce IFN-, IL-17, and TNF-. The ability of IL-6⁺ DC^XAb and the inability of IL-6^–/– DC^XAb vaccines to protect animals from lethal melanoma suggest that exogenously modulated DC can reprogram host Tregs. In support of this hypothesis and as a test for Ag specificity, transfer of DC^XAb into RIP-OVA mice causes a break in immune tolerance, inducing diabetes. Conversely, adoptive transfer of reprogrammed Tregs but not similarly treated CD25^– T cells into naive RIP-OVA mice is also sufficient to cause autoimmune diabetes. Yet, treatment of normal mice with B7-DC XAb fails to elicit generalized autoimmunity. The finding that mature Tregs can be reprogrammed into competent effector cells provides new insights into the plasticity of T cell lineage, underscores the importance of DC-T cell interaction in balancing immunity with tolerance, points to Tregs as a reservoir of autoimmune effectors, and defines a new approach for breaking tolerance to self Ags as a strategy for cancer immunotherapy.

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 funded by Grants R01 CA104996 and R01 HL077296 from the National Institutes of Health (to L.R.P.).

² Address correspondence and reprint requests to Dr. Larry R. Pease, Department of Immunology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail address: pease.larry{at}mayo.edu

³ Abbreviations used in this paper: Treg, T regulatory cell; DC, dendritic cell; RIP, rat insulin promoter; B7-DC XAb, B7-DC cross-linking Ab; DC^XAb, B7-DC XAb-activated DC; DC^cntrl, isotype control Ab-treated DC; WT, wild type.

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The JI 2008 181: 2939-2940. [Full Text]  

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