CD4(+)T cells mediate systemic and local immune changes and pain symptoms in the rat model of temporomandibular disorders related pain

J Headache Pain. 2026 Jun 12. doi: 10.1186/s10194-026-02422-y. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Immune cells involved in pain has received increasing attention, but the available literature on the role of T cells in temporomandibular disorders (TMD) related pain is limited. Our previous study has showed that elevated expression of HLA DR⁺ CD4⁺ T cell may increase the risk of TMD-related pain. In the present study, we aimed to investigate CD4⁺ T cell-mediated systemic and local immune changes in the rat model of TMD-related pain via CD4⁺ T cell depletion, and clarify the immunological contribution of CD4⁺ T cell on TMD-related pain.

METHODS: A rat model of occlusal interference was established to induce TMD-related pain. Animals were divided into three Groups: control (Group1), occlusal interference (Group2), and occlusal interference with CD4⁺ T cell depletion (Group3). Systemic CD4⁺ T cell proportions were verified by flow cytometry at day3, 6, 14. Pain-related behavior was assessed by von Frey testing daily, and the circulating levels of cortisol, TNF-α, IL-6, IL-17 A, and IFN-γ levels quantified by ELISA at day 3, 10, 15. In the end, local inflammatory cytokine expression patterns in condylar tissues were examined by immunofluorescence staining.

RESULTS: Occlusal interference model successfully mimicked significant TMD-related pain with a sharply increase reaching its peak at day 6 followed by a gradual decline, but at lower level of pain in Group3. The circulating level of IL-17 A rapidly rise at the initial phase, then stabilized and declined eventually despite of CD4⁺ T cell depletion or not. Levels of cortisol and TNF-α were significantly decreased at the end of the study in Group 3. Immunofluorescence analysis of condylar tissues revealed substantial up-regulation of TNF-α, IL-6 and IFN-γ in Group 2, which was significantly alleviated in Group 3.

CONCLUSION: This study demonstrated IL-17 A increased with pain independent of CD4⁺T cells at the early stage. But consistently lower pain sensitivity, reduced systemic and local inflammatory cytokines in the later were identified after CD4 + T cell depletion. So we suggest that CD4⁺ T cells are important to maintain TMD-related pain and central to the late-phase immunological cascade in this model. More underlying mechanism of CD4⁺ T cells involved in TMD-related pain warrant further investigations.

PMID:42286475 | DOI:10.1186/s10194-026-02422-y