Myelin-reactive, TGF-β-induced regulatory T cells can be programmed to develop Th1-like effector function but remain less proinflammatory than myelin-reactive Th1 effectors and can suppress pathogenic T cell clonal expansion in vivo

Richard A. O'Connor, Melanie D. Leech, Janine Suffner, Guenter J. Haemmerling, Stephen M. Anderton

Research output: Contribution to journalArticlepeer-review

Abstract

Interest in the use of regulatory T cells (Tregs) as cellular therapeutics has been tempered by reports of naturally occurring Tregs losing Foxp3 expression and producing IL-17, raising concerns over a switch to pathogenic function under inflammatory conditions in vivo. TGF-β-induced Tregs (inducible Tregs [iTregs]), generated in large numbers in response to disease-relevant Ags, represent the most amenable source of therapeutic Tregs. Using Foxp3-reporter T cells recognizing myelin basic protein (MBP), we investigated the capacity of iTregs to produce effector-associated cytokines under proinflammatory cytokine conditions in vitro and whether this translated into proinflammatory function in vivo. In contrast with naturally occurring Tregs, iTregs resisted conversion to an IL-17-producing phenotype but were able to express T-bet and to produce IFN-γ. iTregs initiated their T-bet expression during their in vitro induction, and this was dependent on exposure to IFN-γ. IL-12 reignited iTreg expression of T-bet and further promoted iTreg production of IFN-γ upon secondary stimulation. Despite losing Foxp3 expression and expressing both T-bet and IFN-γ, MBP-responsive IL-12-conditioned iTregs induced only mild CNS inflammation and only when given in high numbers. Furthermore, iTregs retained an ability to suppress naive T cell clonal expansion in vivo and protected against the development of experimental autoimmune encephalomyelitis. Therefore, despite bearing predictive hallmarks of pathogenic effector function, previously Foxp3(+) iTregs have much lower proinflammatory potential than that of MBP-responsive Th1 cells. Our results demonstrate that autoprotective versus autoaggressive functions in iTregs are not simply a binary relationship to be determined by their relative expression of Foxp3 versus T-bet and IFN-γ.
Original languageEnglish
Pages (from-to)7235-7243
Number of pages9
JournalJournal of Immunology
Volume185
Issue number12
DOIs
Publication statusPublished - 15 Dec 2010

Keywords

  • Animals
  • Central Nervous System/immunology
  • Central Nervous System/metabolism
  • Central Nervous System/pathology
  • Cytokines/genetics
  • Cytokines/immunology
  • Cytokines/metabolism
  • Encephalomyelitis, Autoimmune, Experimental
  • Forkhead Transcription Factors
  • Gene Expression Regulation/genetics
  • Gene Expression Regulation/immunology
  • Mice
  • Mice, Knockout
  • Myelin Basic Protein/genetics
  • Myelin Basic Protein/immunology
  • Myelin Basic Protein/metabolism
  • T-Lymphocytes, Regulatory
  • Th1 Cells
  • Transforming Growth Factor beta

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