# CD8+ T cell–derived IL-13 increases macrophage IL-10 to resolve neuropathic pain

## TL;DR

CD8+ T cells release IL-13, which helps macrophages produce IL-10 to resolve neuropathic pain after chemotherapy.

## Contribution

The study identifies a novel IL-13/IL-10 pathway involving CD8+ T cells and macrophages that resolves chemotherapy-induced neuropathic pain.

## Key findings

- CD8+ T cells producing IL-13 are essential for resolving chemotherapy-induced peripheral neuropathy.
- IL-13 from CD8+ T cells induces macrophage IL-10 production, which is critical for pain resolution.
- Blocking TIM3 on CD8+ T cells or IL-13 delays pain resolution, highlighting their role in the process.

## Abstract

Understanding the endogenous mechanisms regulating resolution of pain may identify novel targets for treatment of chronic pain. Resolution of chemotherapy-induced peripheral neuropathy (CIPN) after treatment completion depends on CD8+ T cells and on IL-10 produced by other cells. Using Rag2–/– mice lacking T and B cells and adoptive transfer of Il13–/– CD8+ T cells, we showed that CD8+ T cells producing IL-13 were required for resolution of CIPN. Intrathecal administration of anti–IL-13 delayed resolution of CIPN and reduced IL-10 production by dorsal root ganglion macrophages. Depleting local CD206+ macrophages also delayed resolution of CIPN. In vitro, TIM3+CD8+ T cells cultured with cisplatin, apoptotic cells, or phosphatidylserine liposomes produced IL-13, which induced IL-10 in macrophages. In vivo, resolution of CIPN was delayed by intrathecal administration of anti-TIM3. Resolution was also delayed in Rag2–/– mice reconstituted with Havcr2 (TIM3)–/– CD8+ T cells. Our data indicated that cell damage induced by cisplatin activated TIM3 on CD8+ T cells, leading to increased IL-13 production, which in turn induced macrophage IL-10 production and resolution of CIPN. Development of exogenous activators of the IL-13/IL-10 pain resolution pathway may provide a way to treat the underlying cause of chronic pain.