Homogeneous expansion of human T-regulatory cells via tumor necrosis factor receptor 2

Sci Rep. 2013 Nov 6;3:3153. doi: 10.1038/srep03153.

Abstract

T-regulatory cells (T(regs)) are a rare lymphocyte subtype that shows promise for treating infectious disease, allergy, graft-versus-host disease, autoimmunity, and asthma. Clinical applications of T(regs) have not been fully realized because standard methods of expansion ex vivo produce heterogeneous progeny consisting of mixed populations of CD4 + T cells. Heterogeneous progeny are risky for human clinical trials and face significant regulatory hurdles. With the goal of producing homogeneous T(regs), we developed a novel expansion protocol targeting tumor necrosis factor receptors (TNFR) on T(regs). In in vitro studies, a TNFR2 agonist was found superior to standard methods in proliferating human T(regs) into a phenotypically homogeneous population consisting of 14 cell surface markers. The TNFR2 agonist-expanded T(regs) also were functionally superior in suppressing a key T(reg) target cell, cytotoxic T-lymphocytes. Targeting the TNFR2 receptor during ex vivo expansion is a new means for producing homogeneous and potent human T(regs) for clinical opportunities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Cytokines / metabolism
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Interleukin-2 / genetics
  • Interleukin-2 / metabolism
  • Interleukin-2 / pharmacology
  • Receptors, Tumor Necrosis Factor, Type II / agonists
  • Receptors, Tumor Necrosis Factor, Type II / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor, Type II / metabolism*
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Antibodies, Monoclonal
  • Cytokines
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-2
  • Receptors, Tumor Necrosis Factor, Type II
  • Recombinant Proteins
  • TNFRSF1B protein, human
  • Tumor Necrosis Factor-alpha