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

Ahmed Olalekan Bakare; Gerard Limerick; Vasudha Goel; Ratan K Banik; Lei Zheng; Andrew J Shepherd; Kristine Glunde; Qin Zheng; Eellan Sivanesan

doi:10.1177/17448069261418431

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

Mol Pain. 2026 Jan-Dec:22:17448069261418431. doi: 10.1177/17448069261418431. Epub 2026 Jan 14.

Authors

Ahmed Olalekan Bakare¹, Gerard Limerick², Vasudha Goel³, Ratan K Banik⁴, Lei Zheng^{5

6}, Andrew J Shepherd⁷, Kristine Glunde^{6

8

9}, Qin Zheng¹, Eellan Sivanesan¹

Affiliations

¹ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Allina Health Neuroscience Pain and Spine Institute, Minneapolis, MN, USA.
⁴ Department of Anesthesiology, University of Minnesota, Minneapolis, MN, USA.
⁵ Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁷ Laboratories of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

PMID: 41532412
DOI: 10.1177/17448069261418431

Abstract

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.

Keywords: Chemotherapy-induced peripheral neuropathy; T cells; neuropathic pain; paclitaxel.

MeSH terms

Animals
Hyperalgesia / pathology
Macrophages / drug effects
Macrophages / metabolism
Male
Paclitaxel* / adverse effects
Peripheral Nervous System Diseases* / chemically induced
Peripheral Nervous System Diseases* / immunology
Peripheral Nervous System Diseases* / pathology
Rats
Rats, Sprague-Dawley
T-Lymphocytes* / immunology

Substances

Paclitaxel