Imbalance between Th17 and Treg cells may play an important role in the development of chronic unpredictable mild stress-induced depression in mice

Background: Recent data suggest that major depression is potentially associated with dysregulated cytokine production. However, the roles of T helper (Th) cells and their subsets in the development of depression still remain to be determined. The present study assessed changes in Th cell subsets and cytokines during the development of depression in a mouse model.

Methods: Chronic unpredictable mild stress (CUMS) was used to simulate depression behavior in mice. The open field test, sucrose preference, and ingestion were used as evaluative indicators of depressive behavior. During the CUMS protocol, on days 3, 7, 14, and 21, we assessed behavioral changes, cytokine levels in serum or stimulated (CD3/CD28) cell culture medium, and mRNA expression (ELISA, RT-PCR), regulatory T (Treg) and Th17 subsets in spleen (ex vivo, flow cytometry, RT-PCR), and CD3/rIL-23-stimulated Th17 cell proliferation (MTT assay).

Results: The results showed that in the depression model mice, IL-4 mRNA expression and serum levels increased on day 7, while no detectable change was observed in IFN-γ. Notably, a reduced proportion of Th17 cells with decreased proliferation capacity was observed at later stages, in parallel with a decline in serum IL-23 levels. In contrast, an increased Treg cell proportion and increased Foxp3 mRNA expression were observed in the mid-stages. Correlation analysis showed that the proportion of Tregs was correlated negatively with sucrose preference, while the proliferation of Th17 cells was notably correlated positively with sucrose preference. Also, an increased TGF-β level was detected in serum and was believed to be a key factor responsible for the imbalance between Th17 and Treg cells. Furthermore, the sucrose preference in TGF-β type I receptor blockade mice increased considerably, compared with CUMS mice.

Conclusion: These results indicate that in CUMS-induced depression, behavioral changes may closely correlate with the imbalance between Th17 and Treg cell subsets, and TGF-β may be a key regulatory cytokine.