GITR Blockade Facilitates Treg Mediated Allograft Survival

Area of Science:

• Immunology
• Transplantation Biology

Background:

• Transplant tolerance often relies on regulatory T cells (Tregs).
• Innate immune signals can inhibit Treg function, hindering transplant tolerance.
• Glucocorticoid-induced tumor necrosis factor receptor-related (GITR) protein on Tregs inhibits their activity.

Purpose of the Study:

• To investigate if blocking GITR signaling can enhance Treg activity.
• To assess the impact of blocking GITR on allograft survival in an inflammatory setting.

Main Methods:

• Utilized an adoptive transfer model of allograft rejection.
• Compared Treg capacity to prolong graft survival with and without AITRL-Fc, a GITR-binding construct.
• Studied the effects of inflammation and antigen-specific Tregs on graft survival.

Main Results:

• Interruption of GITR-GITR ligand (GITRL) binding by AITRL-Fc led to long-term, Treg-dependent skin graft acceptance.
• This acceptance occurred despite innate immune signals that normally impede Treg activity.

Conclusions:

• The GITR-GITRL interaction is a mechanism by which antigen-presenting cells can suppress Tregs and promote immune responses.
• Blocking GITR-GITRL interaction with AITRL-Fc sustains graft-protective Treg benefits.
• This approach offers a strategy to overcome barriers to transplantation tolerance.