Retinoic acid-responsive CD8 effector T cells are selectively increased in IL-23-rich tissue in gastrointestinal GVHD

Area of Science:

• Immunology
• Transplantation Biology
• Gastroenterology

Background:

• Gastrointestinal (GI) graft-versus-host disease (GVHD) is a significant complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT).
• Retinoic acid (RA) is known to enhance GI-GVHD in mice through T cells expressing the RA receptor-α (RARα).
• The specific role of RA-responsive cells in human GI-GVHD has not been clearly defined.

Purpose of the Study:

• To investigate the presence and characteristics of RA-responsive T cells in human GI-GVHD.
• To determine the impact of RA on human T-cell alloresponses in the context of GI-GVHD.
• To identify potential therapeutic targets for GI-GVHD.

Main Methods:

• Utilized conventional and novel sequential immunostaining and flow cytometry techniques.
• Analyzed tissues and blood samples from patients who underwent allo-HSCT.
• Employed a targeted candidate protein approach to predict T-cell phenotypes.

Main Results:

• Expression of RARα was upregulated in human mononuclear cells upon RA exposure.
• RARαhi mononuclear cells, increased in GI-GVHD tissues, correlated with disease severity and mortality.
• Identified a specific population of RARαhi CD8 T cells expressing T-bet and IL-23R, which were enriched in GI-GVHD tissues and blood.
• Demonstrated that RA promotes alloreactive, GI-tropic RARαhi CD8 effector T cells, with IL-23 further enhancing this effect.

Conclusions:

• A distinct population of RA-responsive effector T cells (RARαhi CD8 T cells) is selectively expanded in human GI-GVHD.
• These cells exhibit a specific phenotype (T-bet+, IL-23R+) and are associated with disease severity.
• This RA-responsive T-cell population represents a promising novel therapeutic target for managing GI-GVHD.