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CD28 costimulation is essential for human T regulatory expansion and function.

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CD28 costimulation is crucial for expanding human T regulatory cells (Tregs) and maintaining their suppressive function. This finding is vital for developing Treg-based therapies to manage immune responses.

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Area of Science:

  • Immunology
  • Cell Biology
  • Translational Medicine

Background:

  • Peripheral blood T regulatory cells (Tregs) play a critical role in immune homeostasis.
  • The specific costimulatory signals required for optimal Treg expansion and function remain incompletely understood.

Purpose of the Study:

  • To elucidate the costimulatory requirements for expanding human peripheral blood Tregs.
  • To assess the impact of different costimulatory molecules on Treg suppressive function and replicative potential.

Main Methods:

  • Utilized artificial antigen-presenting cells (aAPCs) to provide defined costimulatory signals.
  • Cultured human Tregs with various costimulatory molecules (CD28, ICOS, OX40, 4-1BB, CD27, CD40L) in combination with rapamycin.
  • Assessed Foxp3 expression, in vitro suppressive function, and in vivo efficacy in a xenogeneic graft-versus-host disease (xeno-GvHD) model.

Main Results:

  • CD28 costimulation, in the presence of rapamycin, was essential for maintaining high Foxp3 expression and in vitro suppressive function.
  • CD28 costimulation with rapamycin generated Tregs that effectively suppressed xeno-GvHD in immunodeficient mice.
  • While OX40 costimulation enhanced proliferation, it diminished Foxp3 expression and suppressive function in CD28-costimulated Tregs.
  • Demonstrated >1000-fold Treg expansion within 3 weeks using CD28 costimulation and rapamycin.

Conclusions:

  • Human postthymic Tregs require CD28 costimulation to expand and maintain potent suppressive function.
  • The costimulatory requirements for Treg expansion differ from those of T effector cells.
  • These findings have significant implications for the therapeutic application of Tregs in managing immune-related disorders.