Targeting the pentose phosphate pathway mitigates graft-versus-host disease by rewiring alloreactive T cell...

Area of Science:

• Immunology
• Metabolic pathways
• Cellular metabolism

Background:

• Glycolysis fuels T cells in acute graft-versus-host disease (aGvHD), but downstream glucose metabolism roles are unclear.
• Targeting glycolysis is toxic; alternative pathways require investigation for aGvHD modulation.
• The pentose phosphate pathway (PPP) is a key alternative glucose metabolism route.

Purpose of the Study:

• To investigate the role of the pentose phosphate pathway (PPP) in T cell proliferation during aGvHD.
• To identify potential therapeutic targets within the PPP for mitigating aGvHD.
• To assess the impact of PPP inhibition on graft-versus-tumor (GvT) effects.

Main Methods:

• Single-cell RNA sequencing to identify upregulated pathways in T cells during allogeneic hematopoietic cell transplantation (allo-HCT).
• Murine models of aGvHD and xenogeneic GvHD to assess disease severity and mortality.
• Functional assays to evaluate T cell proliferation and apoptosis upon PPP blockade.
• Pharmacological inhibition of 6-phosphogluconate dehydrogenase (6PGD) using 6-aminonicotinamide (6AN).

Main Results:

• PPP was upregulated in allogeneic T cells post-allo-HCT.
• Donor T cell deficiency in 6PGD significantly reduced aGvHD severity and mortality.
• PPP blockade caused proliferation arrest without inducing apoptosis, shifting metabolism from glycolysis.
• 6AN treatment effectively reduced aGvHD and xenogeneic GvHD lethality.
• 6PGD inhibition preserved the graft-versus-tumor (GvT) effect.

Conclusions:

• The PPP is a critical regulator of allogeneic T cell proliferation and differentiation in aGvHD.
• 6PGD is a promising therapeutic target for reducing aGvHD.
• Targeting 6PGD offers a strategy to mitigate aGvHD while preserving beneficial GvT responses.