T cell-dependent modulation of pain behaviors in a rat model of recurring paclitaxel-induced peripheral neuropathy

Advances in preventing or treating chemotherapy-induced peripheral neuropathy (CIPN) have been limited because most preclinical models do not capture the repeated cycles of chemotherapy exposure common in clinical practice. Consequently, the mechanisms driving CIPN across successive chemotherapy cycles remain incompletely understood. Here, we investigated the contribution of T cells to recurrent paclitaxel (PTX)-induced peripheral neuropathy (PIPN) using homozygous RNU rats (T cell-deficient) and heterozygous littermates (T cell-competent). PTX (8 mg/kg total) was administered intraperitoneally over two treatment cycles to model repeated chemotherapy exposure and its effects on neuropathic pain. Pain sensitivity testing with von Frey filaments, dry-ice, and acetone assays revealed distinct pain phenotypes across cycles. Mechanical allodynia was transient, resolving between cycles, with a smaller reduction in mechanical withdrawal threshold during the observed period following the second cycle, independent of T cell status. In contrast, cold hyperalgesia persisted in T cell-competent rats but did not reach significance in T cell-deficient rats, whereas cold allodynia was transient, resolving between cycles, and developed exclusively in T cell-competent rats. T cell frequencies in peripheral neural tissues were higher after the second PTX cycle than after the first, while natural killer cell populations showed T cell- and tissue-specific differences across cycles. CD163⁺ M2-like macrophage abundance remained relatively stable across cycles in peripheral neural tissues, whereas CD206⁺ M2-like and CD86⁺ M1 macrophage populations showed tissue-specific changes. Repeated exposure also reduced satellite glial cell gliosis and was associated with gene-specific transcriptional changes, including T cell-dependent effects linked to immune-glial signaling in the sciatic nerve. Together, these findings indicate that repeated paclitaxel exposure produces distinct transient and persistent pain phenotypes and engages tissue-specific neuroimmune mechanisms, with T cells selectively shaping sensory outcomes in PIPN.