The influence of T cells in painful paclitaxel-induced peripheral neuropathy: Key roles in cold hypersensitivity and immune modulation

Background: Conflicting reports on the role of T cells in chemotherapy-induced peripheral neuropathy (CIPN) create uncertainty regarding their influence on neuropathic pain, hindering progress in CIPN treatment and prevention. This study compares T-cell competent (RNU+/-) and T-cell deficient (RNU-/-) rats to explore the role of T cells in painful paclitaxel (PTX)-induced peripheral neuropathy (PIPN). Methods: Adult male, T-cell competent and T-cell deficient rats were treated with paclitaxel (8 mg/kg i.p. total dose) in a model of non-squamous cell lung carcinoma. Reflexive (mechanical, heat, cold), spontaneous (burrowing, gait), and non-reflexive (open field) pain behaviors were evaluated before and after the induction of PIPN. Immunohistochemistry (CD206, CD68, CX3CL1, CX3CR1) and flow cytometry (CD3, CD161a, CD45RA, CD163, CD86) were employed to assess macrophages and lymphocytes in the dorsal root ganglia (DRG), sciatic nerves, and spleen. Results: Our findings demonstrate that T cells are essential for the development of PTX-induced cold hypersensitivity. T cells reduced the onset-intensity of mechanical hypersensitivity and decreased burrowing activity. Flow cytometry revealed an increased CD4+/CD8+ T-cell ratio in PTX-treated T-cell competent rats in the DRG, sciatic nerve, and spleen. Additionally, PTX treatment led to a reduction in B cells and a shift in macrophage polarization towards the M1 phenotype, reducing the M2/M1 ratio, which was independent of T cells. However, an increase in M2 macrophages (M2Ƴ and M2a) in sciatic nerves was dependent on the absence of T cells. Paclitaxel decreases the expression of CX3CR1 in the DRG in a T-cell-dependent manner but increases CX3CR1 expression in the sciatic nerve independently of T cells. Natural killer (NK) cell levels were reduced in PTX-treated, T-cell deficient rats but remained unchanged in T-cell competent rats. Conclusions: T cells are essential for the development of cold hypersensitivity and reduce mechanical hypersensitivity and spontaneous pain at the onset of CIPN. These T-cell dependent effects may be mediated by an increased CD4+/CD8+ T-cell ratio, decreased M2Ƴ macrophages in sciatic nerves, and maintenance of NK cells in T-cell competent rats. supported by National Institutes of Health CA255428 (E.S.) and The Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University (E.S.) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.