Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice

Immunity. 2010 Dec 14;33(6):942-54. doi: 10.1016/j.immuni.2010.11.022. Epub 2010 Dec 9.

Abstract

Foxp3(+) regulatory T (Treg) cells can undergo reprogramming into a phenotype expressing proinflammatory cytokines. However, the biologic significance of this conversion remains unclear. We show that large numbers of Treg cells undergo rapid reprogramming into activated T helper cells after vaccination with antigen plus Toll-like receptor 9 (TLR-9) ligand. Helper activity from converted Treg cells proved essential during initial priming of CD8(+) T cells to a new cross-presented antigen. Help from Treg cells was dependent on CD40L, and (unlike help from conventional non-Treg CD4(+) cells) did not require preactivation or prior exposure to antigen. In hosts with established tumors, Treg cell reprogramming was suppressed by tumor-induced indoleamine 2,3-dioxygenase (IDO) and vaccination failed because of lack of help. Treg cell reprogramming, vaccine efficacy, and antitumor CD8(+) T cell responses were restored by pharmacologic inhibition of IDO. Reprogrammed Treg cells can thus participate as previously unrecognized drivers of certain early CD8(+) T cell responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Transdifferentiation / drug effects
  • Cells, Cultured
  • Cross-Priming* / drug effects
  • Forkhead Transcription Factors / biosynthesis
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors
  • Lymphocyte Activation / drug effects
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / immunology*
  • Mice
  • Mice, Inbred Strains
  • Oligodeoxyribonucleotides / administration & dosage
  • T-Lymphocytes, Helper-Inducer / drug effects
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / metabolism*
  • T-Lymphocytes, Helper-Inducer / pathology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • T-Lymphocytes, Regulatory / pathology
  • Toll-Like Receptor 9 / immunology
  • Tryptophan / analogs & derivatives
  • Tryptophan / pharmacology

Substances

  • Antigens
  • CPG-oligonucleotide
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Oligodeoxyribonucleotides
  • Toll-Like Receptor 9
  • Tryptophan