CD8⁺ T cells and endogenous IL-10 are required for resolution of chemotherapy-induced neuropathic pain

Chemotherapy-induced peripheral neuropathy (CIPN), characterized by pain and numbness in hands and feet, is acommonside effect of cancer treatment. In most patients, symptoms of CIPN subside after treatment completion. However, in a substantial subgroup, CIPN persists long into survivorship. Impairment in pain resolution pathways may explain persistent CIPN. We investigated the contribution of T cells and endogenous interleukin (IL)-10 to resolution of CIPN. Paclitaxel-induced mechanical allodynia was prolonged in T-celldeficient (Rag1^-/-) mice compared with wild-type (WT) mice. There were no differences between WT and Rag1^-/- mice in severity of paclitaxel-induced mechanical allodynia. Adoptive transfer of either CD3⁺ or CD8⁺, but not CD4⁺, T cells to Rag1^-/-mice normalized resolution of CIPN. Paclitaxel treatment increased the number of T cells in lumbar dorsal root ganglia (DRG), where CD8⁺T cells were the major subset. Inhibition of endogenous IL-10 signaling by intrathecal injection of anti-IL-10 toWTmice or Rag1^-/- mice reconstituted with CD8⁺ T cells delayed recovery from paclitaxel-induced mechanical allodynia. Recovery was also delayed in IL-10 knock-out mice. Conversely, administration of exogenous IL-10 attenuated paclitaxel-induced allodynia. In vitro, IL-10 suppressed abnormal paclitaxelinduced spontaneous discharges in DRG neurons. Paclitaxel increased DRG IL-10 receptor expression and this effect requires CD8⁺ T cells. In conclusion,weidentified a novel mechanism for resolution of CIPN that requires CD8⁺Tcells and endogenous IL-10.Wepropose that CD8⁺ T cells increase DRG IL-10 receptor expression and that IL-10 suppresses the abnormal paclitaxel-induced spontaneous discharges by DRG neurons to promote recovery from CIPN.