T cells modulate the development and maintenance of painful paclitaxel-induced peripheral neuropathy in RNU rats

The role of T cells in chemotherapy-induced peripheral neuropathy (CIPN) is complex and shaped by biological and experimental factors, including sex, hormonal status, genetic background, and cancer model. This complexity has contributed to inconsistent findings among studies, limiting therapeutic progress. In this study, we investigate how T cells contribute to painful paclitaxel (PTX)-induced peripheral neuropathy (PIPN). Adult male T cell-competent (RNU^+/-) and T cell-deficient (RNU^-/-) rats were subcutaneously inoculated with tumor cells and subsequently treated with intraperitoneal PTX (8 mg/kg total dose). Reflexive (mechanical, heat, cold) and non-reflexive (burrowing, gait) pain behaviors were assessed from baseline through week 6. Immunohistochemistry (CD68, CX3CR1, CD206) and flow cytometry (CD163, CD86, CD11b/c, CD3, CD161a, CD45RA) were used to assess macrophage and lymphocyte populations. T cell-competent, but not -deficient, rats developed and maintained cold hypersensitivity following PTX. T cells also reduced the onset intensity of PTX-induced mechanical hypersensitivity. In T cell-competent rats, PTX reduced T and B cell counts and increased the CD4+/CD8+ T cell ratio across DRG, sciatic nerve, and spleen. PTX shifted macrophage polarization toward the M1 phenotype and reduced the M2/M1 ratio, independent of T cells. However, M2 macrophages (M2γ and M2a) increased specifically in the sciatic nerves of T cell-deficient rats. Additionally, natural killer (NK) cells decreased in PTX-treated, T cell-deficient rats but remained unchanged in T cell-competent rats. These findings highlight the complex role of T cells in PIPN. In PIPN, T cells play a critical role in driving PTX-induced cold hypersensitivity. A decrease in their number worsens pain intensity, possibly by altering the CD4+/CD8+ T cell balance. In contrast, NK cell reductions in T cell-deficient rats may contribute to hypersensitivity in the absence of T cells.