CD3+ T cells are critical for the resolution of comorbid inflammatory pain and depression-like behavior

Background

Chronic pain and depression often co-occur. The mechanisms underlying this comorbidity are incompletely understood. Here, we investigated the role of CD3⁺ T cells in an inflammatory model of comorbid persistent mechanical allodynia, spontaneous pain, and depression-like behavior in mice.

Methods

C57Bl/6 wt and Rag2^−/− mice were compared in their response to intraplantar administration of complete Freund’s adjuvant (CFA). Mechanical allodynia, spontaneous pain and depression-like behavior were assessed by von Frey, conditioned place preference and forced swim test respectively.

Results

Resolution of mechanical allodynia, spontaneous pain, and depression-like behavior was markedly delayed in Rag2^−/− mice that are devoid of adaptive immune cells. Reconstitution of Rag2^−/− mice with CD3⁺ T cells from WT mice before CFA injection normalized the resolution of indicators of pain and depression-like behavior. T cells did not contribute to onset or severity of indicators of pain and depression-like behavior. The lack of T cells did not affect cytokine expression in the paw, spinal cord and brain, indicating that the delayed resolution was not resulting from prolonged (neuro)inflammation.

Conclusions

Our findings show that T cells are critical for the natural resolution of mechanical allodynia, spontaneous pain, and depression-like behavior after an inflammatory challenge. Dysregulation of this T cell-mediated resolution pathway could contribute to the comorbidity of chronic pain and depression.

Significance

Chronic pain and depression are frequently associated with signs of inflammation. However, general immunosuppression is not sufficient to resolve comorbid pain and depression. Here we demonstrate that T cells are required for resolution of comorbid persistent mechanical allodynia, spontaneous pain, and depression in a model of peripheral inflammation, indicating the immune system can contribute to both onset and resolution of these comorbidities. Enhancing pro-resolution effects of T cells may have a major impact to treat patients with comorbid persistent pain and depression.