4-1BB Signaling in Conventional T Cells Drives IL-2 Production That Overcomes CD4+CD25+FoxP3+ T Regulatory Cell Suppression

PLoS One. 2016 Apr 6;11(4):e0153088. doi: 10.1371/journal.pone.0153088. eCollection 2016.

Abstract

Costimulation with the recombinant SA-4-1BBL agonist of 4-1BB receptor on conventional CD4+ T cells (Tconvs) overcomes the suppression mediated by naturally occurring CD4+CD25+FoxP3+ T regulatory cells (Tregs). The mechanistic basis of this observation has remained largely unknown. Herein we show that Tconvs, but not Tregs, are the direct target of SA-4-1BBL-mediated evasion of Treg suppression. IL-2 produced by Tconvs in response to 4-1BB signaling is both necessary and sufficient for overcoming Treg suppression. Supernatant from Tconvs stimulated with SA-4-1BBL contains high levels of IL-2 and overcomes Treg suppression in ex vivo Tconv:Treg cocultures. Removal of IL-2 from such supernatant restores Treg suppression and repletion of Tconv:Treg cocultures with exogenous recombinant IL-2 overcomes suppression. This study establishes 4-1BB signaling as a key circuit that regulates physical and functional equilibrium between Tregs and Tconvs with important implications for immunotherapy for indications where a fine balance between Tregs and Teffs plays a decisive role.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / immunology*
  • Forkhead Transcription Factors / immunology*
  • Humans
  • Immunophenotyping
  • Interleukin-2 / biosynthesis*
  • Mice
  • Mice, Inbred C57BL
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / metabolism*

Substances

  • Antigens, CD
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-2
  • TNFRSF9 protein, human
  • Tumor Necrosis Factor Receptor Superfamily, Member 9

Grants and funding

This work was supported by the Commonwealth of Kentucky Research Challenge Trust Fund and the Keck Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.