2. Academic Validation
  3. Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells

Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells

  • Nat Immunol. 2014 May;15(5):473-81. doi: 10.1038/ni.2849.
Shawn A Mahmud 1,  Luke S Manlove 1,  Heather M Schmitz 1,  Yan Xing 1,  Yanyan Wang 2,  David L Owen 1,  Jason M Schenkel 3,  Jonathan S Boomer 4,  Jonathan M Green 5,  Hideo Yagita 6,  Hongbo Chi 2,  Kristin A Hogquist 1,  Michael A Farrar 1
Affiliations

Affiliations

  • 1 Center for Immunology, Masonic Cancer Center, and the Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
  • 2 Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 3 Department of Microbiology, University of Minnesota, Minneapolis, Minnesota, USA.
  • 4 Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
  • 5 1] Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA. [2] Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
  • 6 Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
PMID: 24633226 DOI: 10.1038/ni.2849
Abstract

Regulatory T cells (Treg cells) express members of the tumor-necrosis factor (TNF) receptor superfamily (TNFRSF), but the role of those receptors in the thymic development of Treg cells is undefined. We found here that Treg cell progenitors had high expression of the TNFRSF members GITR, OX40 and TNFR2. Expression of those receptors correlated directly with the signal strength of the T cell antigen receptor (TCR) and required the coreceptor CD28 and the kinase TAK1. The neutralization of ligands that are members of the TNF Superfamily (TNFSF) diminished the development of Treg cells. Conversely, TNFRSF agonists enhanced the differentiation of Treg cell progenitors by augmenting responsiveness of the interleukin 2 receptor (IL-2R) and transcription factor STAT5. Costimulation with the ligand of GITR elicited dose-dependent enrichment for cells of lower TCR affinity in the Treg cell repertoire. In vivo, combined inhibition of GITR, OX40 and TNFR2 abrogated the development of Treg cells. Thus, expression of members of the TNFRSF on Treg cell progenitors translated strong TCR signals into molecular parameters that specifically promoted the development of Treg cells and shaped the Treg cell repertoire.

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