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

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.

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.

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.

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.