Role of T and B lymphocyte cannabinoid type 1 and 2 receptors in major depression and suicidal behaviors: effects of in vitro cannabidiol administration.

Early flow cytometry studies revealed T cell activation in major depressive disorder (MDD) (Maes et al., 1990-1993). MDD is characterised by activation of the immune-inflammatory response system (IRS) and the compensatory immunoregulatory system (CIRS), including deficits in T regulatory (Treg) cells. This study examines the number of cannabinoid type 1 (CB1) and type 2 (CB2) receptor bearing T/B lymphocytes in MDD, and the effects of in vitro cannabidiol (CBD) administration on CB1/CB2. Using flow cytometry, we determined the percentage of CD20+CB2+, CD3+CB2+, CD4+CB2+, CD8+CB2 and FoxP3+CB1+ cells in 19 healthy controls and 29 MDD patients in 5 conditions: baseline, stimulation with anti-CD3/CD28 with or without 0.1 {micro}g/mL, 1.0 {micro}g/mL or 10.0 {micro}g/mL CBD. We found that CB2+ was significantly higher in CD20+ than CD3+ and CD4+, and CD8+ cells. Stimulation with anti-CD3/CD8 beads increases the number of CB2-bearing CD3+, CD4+, and CD8+ cells, as well as CB1-bearing FoxP3+ cells. There was an inverse association between the number of reduced CD4+CB2+ and IRS profiles, including M1 macrophage, T helper-(Th)-1 and Th-17 phenotypes. MDD is characterized by lowered basal FoxP3+CB1+% and higher CD20+CB2+%. 33.2% of the variance in the depression phenome (including severity of depression, anxiety, and current suicidal behaviors) is explained by CD20+CB2+% (positively) and CD3+CB2+% (inversely). All 5 immune cell populations were significantly increased by 10 {micro}g/mL CBD administration. In conclusion, reductions in FoxP3+CB1+% and CD3+/CD4+CB2+% contribute to deficits in immune homeostasis in MDD, while increased CD20+CB2+% may contribute to the pathophysiology of MDD by activating T-independent humoral immunity. SummationsO_LILowered CD4+CB2+ T cells are associated with increased immune-inflammatory responses (IRS) in major depressive disorder (MDD) C_LIO_LILowered CD3+CB2+% and increased CD20+CB2+% predict severity of depression and suicidal behaviors C_LIO_LILowered CD3/CD4+CB2+ may impact the immune homeostatic processes leading to enhanced IRS in MDD C_LIO_LIIncreased CD20+CB2+% may activate T-independent humoral immunity and enhance IRS responses. C_LI ConsiderationsO_LIDepletion of CB1 bearing T regulatory and CB2 bearing T and T helper cells and increased CB2+ bearing B cells are new drug targets in MDD. C_LIO_LIThe findings deserve replication in other countries and cultures. C_LIO_LIFuture research should examine CB2 bearing macrophages, dendritic cells, and natural killer cells in MDD C_LI