T cell activation via the CD40 ligand and transferrin receptor and deficits in T regulatory cells are associated with major depressive disorder and severity of depression

Major depressive disorder (MDD) is associated with T cell activation (Maes et al. 1990-1993), but no studies have examined the combined effects of T cell activation and deficits in T regulatory (Treg) cells on the severity of acute phase MDD. Using flow cytometry, we determined the percentage and median fluorescence intensity of CD69, CD71, CD40L, and HLADR-bearing CD3+, CD4+, and CD8+ cells, and cannabinoid type 1 receptor (CB1), CD152 and GARP-bearing CD25+FoxP3 T regulatory (Treg) cells in 30 MDD patients and 20 healthy controls in unstimulated and stimulated (anti-CD3/CD28) conditions. Based on cytokine levels, we assessed M1 macrophage, T helper (Th)-1, immune-inflammatory response system (IRS), T cell growth, and neurotoxicity immune profiles. We found that the immune profiles (including IRS and neurotoxicity) were significantly predicted by decreased numbers of CD152 or GARP-bearing CD25+FoxP3 cells or CD152 and GARP expression in combination with increases in activated T cells (especially CD8+CD40L+ percentage and expression). MDD patients showed significantly increased numbers of CD3+CD71+, CD3+CD40L+, CD4+CD71+, CD4+CD40L+, CD4+HLADR+, and CD8+HLADR+ T cells, increased CD3+CD71+, CD4+CD71+ and CD4+HLADR+ expression, and lowered CD25+FoxP3 expression and CD25+FoxP+CB1+ numbers as compared with controls. The Hamilton Depression Rating Scale score was strongly predicted (between 30-40% of its variance) by a lower number of CB1 or GARP-bearing Treg cells and one or more activated T cell subtypes (especially CD8+CD40L+). In conclusion, T helper and cytotoxic cell activation coupled with lowered Treg homeostatic defenses are key components of MDD and contribute towards greater immune responses and consequent neuroimmunotoxicity.