STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function.

Area of Science:

• Immunology
• Transplantation Immunology
• Innate Immunity

Background:

• Stimulator of interferon genes (STING) signaling is crucial for innate immune responses.
• STING's role in host cells during allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease (GVHD) is not fully understood.
• Host hematopoietic antigen-presenting cells (APCs) are critical for initiating GVHD.

Purpose of the Study:

• To investigate the function of STING in host hematopoietic APCs during GVHD.
• To determine if STING regulates T-cell allogeneic responses after allo-HCT.

Main Methods:

• Murine models of allo-HCT were used to study STING's role in hematopoietic APCs.
• Bone marrow chimeras were employed to pinpoint STING's cell-specific effects.
• Pharmacologic STING agonists were administered to assess therapeutic potential.

Main Results:

• STING-deficient recipients exhibited more severe GVHD, primarily due to STING's absence in host hematopoietic cells.
• STING on host CD11c+ cells suppressed allogeneic T-cell responses.
• STING deficiency increased APC survival, activation, and function, promoting T-cell expansion and migration, thus exacerbating GVHD.
• STING agonist treatment reduced GVHD mortality.

Conclusions:

• STING in host hematopoietic APCs plays a critical suppressive role in GVHD pathogenesis.
• STING regulates T-cell allogeneic responses by modulating APC activity.
• STING activation represents a promising therapeutic strategy for mitigating GVHD after allo-HCT.