Abstract
Regulatory T cells are essential to maintain immune homeostasis and prevent autoimmunity. Therapy with in vitro expanded human nTRegs is being tested to prevent graft versus host disease, which is a major cause for morbidity and mortality associated with hematopoietic stem cell transplantation. Their usefulness in therapy will depend on their capacity to survive, migrate appropriately and retain suppressive activity when introduced into a transplant recipient. The lack of a suitable animal model for studying the in vivo reconstitutive capability of human nTRegs is a major impediment for investigating the behavior of adoptively transferred nTRegs in vivo. We show that injection of a plasmid encoding human IL-2 is necessary and sufficient for long term engraftment of in vitro expanded nTRegs in NOD-SCID IL2rγcnull mice. We also demonstrate that these in vivo reconstituted TRegs traffic to different organs of the body and retain suppressive function. Finally, in an IL-2 accelerated GVHD model, we show that these in vivo reconstituted TRegs are capable of preventing severe xenogenic response of human PBMCs. Thus, this novel ‘hu-TReg mouse’ model offers a pre-clinical platform to study the in vivo function and stability of human nTRegs and their ability to modulate autoimmune diseases and GVHD.
Highlights
Arising T regulatory cells which originate in the thymus are a subset of CD4+ T cells, which are critical both for suppressing autoreactive lymphocyte responses and for preventing exaggerated antigen-specific immune responses
Their importance is clearly illustrated by lethal systemic autoimmunity and lymphoproliferative disease observed in humans with mutated forkhead box P3 transcription factor (Foxp3) gene and in Foxp3deficient mice [1,2,3]. Naturally arising T regulatory cells (nTRegs) are characterized by the coexpression of Foxp3 and interleukin-2Ra chain CD25
The lymphopenic environment in NOD-SCID IL2rccnull mice is considered conducive to homeostatic expansion of transferred human T cells, unlike conventional T cells, TRegs at a 1:5 (TReg) are unlikely to engraft in the absence of an exogenous source of IL-2
Summary
Arising T regulatory cells (nTRegs) which originate in the thymus are a subset of CD4+ T cells, which are critical both for suppressing autoreactive lymphocyte responses and for preventing exaggerated antigen-specific immune responses. Their importance is clearly illustrated by lethal systemic autoimmunity and lymphoproliferative disease observed in humans with mutated forkhead box P3 transcription factor (Foxp3) gene and in Foxp3deficient mice [1,2,3]. Using anti-CD3/CD28 expander dynabeads and IL-2 in presence of rapamycin, we were able to achieve hundred-fold expansion of nTRegs that retained their phenotype and suppressive function with no evidence of conversion to inflammatory effector or Th17 T cells [5]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call