Reprogrammed FoxP3+ T regulatory cells become IL-17+ antigen-specific autoimmune effectors in vitro and in vivo

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

Research output: Contribution to journalArticle

98 Scopus citations

Abstract

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 (DCXAb) can reprogram Tregs into T effector cells. Down-regulation of FoxP3 expression after either in vitro or in vivo Treg-DCXAb 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-γ, IL-17, and TNF-α. The ability of IL-6+ DCXAb and the inability of IL-6-/-DCXAb 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 DCXAb 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.

Original languageEnglish (US)
Pages (from-to)3137-3147
Number of pages11
JournalJournal of Immunology
Volume181
Issue number5
DOIs
StatePublished - Sep 1 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Radhakrishnan, S., Cabrera, R., Schenk, E. L., Nava-Parada, P., Bell, M. P., Van Keulen, V. P., Marler, R. J., Felts, S. J., & Pease, L. R. (2008). Reprogrammed FoxP3+ T regulatory cells become IL-17+ antigen-specific autoimmune effectors in vitro and in vivo. Journal of Immunology, 181(5), 3137-3147. https://doi.org/10.4049/jimmunol.181.5.3137