Therapeutic effects of stress-programmed lymphocytes transferred to chronically stressed mice

• Rag2−/− mice lacking an adaptive immune system have normal affect and hippocampal cell proliferation.
• Chronic restraint stress creates an anxious and depressed state in both Rag2−/− and control mice.
• Transfer of lymphocytes from stressed mice into stressed Rag2−/− mice restores normal affect.
• Transferred lymphocytes populate lymphoid organs, choroid plexus, and meninges.

Our group has recently provided novel insights into a poorly understood component of intercommunication between the brain and the immune system by showing that psychological stress can modify lymphocytes in a manner that may boost resilience to psychological stress. To demonstrate the influence of the adaptive immune system on mood states, we previously showed that cells from lymph nodes of socially defeated mice, but not from unstressed mice, conferred anxiolytic and antidepressant-like effects and elevated hippocampal cell proliferation when transferred into naïve lymphopenic Rag2−/− mice. In the present study, we asked whether similar transfer could be anxiolytic and antidepressant when done in animals that had been rendered anxious and depressed by chronic psychological stress. First, we demonstrated that lymphopenic Rag2−/− mice and their wild-type C57BL/6 mouse counterparts had similar levels of affect normally. Second, we found that following chronic (14 days) restraint stress, both groups displayed an anxious and depressive-like phenotype and decreased hippocampal cell proliferation. Third, we showed that behavior in the open field test and light/dark box was normalized in the restraint-stressed Rag2−/− mice following adoptive transfer of lymph node cells from green fluorescent protein (GFP) expressing donor mice previously exposed to chronic (14 days) of social defeat stress. Cells transferred from unstressed donor mice had no effect on behavior. Immunolabeling of GFP+ cells confirmed that tissue engraftment had occurred at 14 days after transfer. We found GFP+ lymphocytes in the spleen, lymph nodes, blood, choroid plexus, and meninges of the recipient Rag2−/− mice. The findings suggest that the adaptive immune system may play a key role in promoting recovery from chronic stress. The data support using lymphocytes as a novel therapeutic target for anxiety states.