Damage-induced pyroptosis drives endogenous thymic regeneration by activating the purinergic receptor P2Y2

TL;DR

This study shows that thymic regeneration after damage is driven by pyroptosis in thymocytes, which activates P2Y2 receptors to promote immune recovery.

Contribution

The novel finding is that pyroptosis in thymocytes triggers P2Y2-mediated thymic regeneration, identifying P2Y2 as a potential therapeutic target.

Findings

CD4+ CD8+ thymocytes undergo pyroptosis after radiation, releasing ATP into the thymic microenvironment.

Extracellular ATP activates P2Y2 on thymic epithelial cells, upregulating FOXN1 and promoting regeneration.

P2Y2 agonists like UTPγS accelerate TEC regeneration in vivo after acute damage.

Abstract

T cell recovery is critical following damage, such as hematopoietic cell transplantation (HCT), with increased reconstitution associated with improved clinical outcomes. Endogenous thymic regeneration, a crucial process for restoring immune competence following cytoreductive therapies such as HCT conditioning, is often delayed, limiting T cell reconstitution. Fully understanding the molecular mechanisms driving regeneration is therefore crucial for uncovering therapeutic targets that can be exploited to enhance thymic function. Here, we identified that CD4+ CD8+ thymocytes rapidly and acutely undergo lytic cell death, specifically pyroptosis, following acute damage caused by ionizing radiation, and release damage-associated molecular patterns (DAMPS) into the thymic microenvironment, including ATP. Extracellular ATP stimulates the P2Y2 purinergic receptor on thymic epithelial cells (TECs)—a stromal cell crucial for supporting T cell development—resulting in the upregulation FOXN1, the master TEC transcription factor. Targeting the P2Y2 receptor with a P2Y2 agonist, UTPγS, promotes rapid regeneration of the TEC compartment in vivo following acute damage. These findings reveal a novel damage-sensing mechanism employed by the thymus where thymocytes adopt an alternative cell death mechanism which promotes thymic repair via P2Y2 signaling in TECs. This work identifies P2Y2 as a promising therapeutic target for enhancing thymus regeneration and improving immune recovery after HCT.

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