STING differentially regulates experimental GVHD mediated by CD8 versus CD4 T cell subsets.

Area of Science:

• Immunology
• Transplantation Biology
• Innate Immunity

Background:

• The stimulator of interferon genes (STING) pathway regulates immune responses and gastrointestinal homeostasis.
• STING's role in major histocompatibility complex (MHC)-matched allogeneic hematopoietic stem cell transplantation (aHSCT)-induced graft-versus-host disease (GVHD) is not well understood.
• Previous studies suggest STING protects against GVHD in MHC-mismatched settings.

Purpose of the Study:

• To investigate the role of STING signaling in MHC-matched aHSCT-induced GVHD.
• To determine the impact of STING activity on immune cell activation and antigen-presenting cell survival post-aHSCT.
• To explore STING as a potential therapeutic target for GVHD management.

Main Methods:

• Utilized mouse models of MHC-matched and MHC-mismatched aHSCT.
• Examined STING signaling in nonhematopoietic cells and intestinal organoid cultures.
• Assessed the impact of STING deficiency and genetic variations on GVHD severity.
• Analyzed donor T cell activation and recipient antigen-presenting cell (APC) survival.

Main Results:

• STING signaling in nonhematopoietic cells exacerbated MHC-matched aHSCT-induced GVHD.
• STING agonists increased type I interferon and MHC class I expression in intestinal organoids.
• Mice with reduced STING activity exhibited less GVHD.
• STING deficiency reduced early donor CD8+ T cell activation and promoted recipient APC survival, leading to increased CD4+ T cell-mediated GVHD in mismatched models.

Conclusions:

• STING plays a dual role in aHSCT outcomes, promoting GVHD in MHC-matched settings but potentially influencing T cell responses differently in mismatched scenarios.
• Targeting STING early after aHSCT could be a strategy to regulate clinical GVHD.
• The donor/recipient MHC disparity significantly influences the effect of the STING pathway on aHSCT outcomes.