CD4⁺ but Not CD8⁺ T Cells Revert the Impaired Emotional Behavior of Immunocompromised RAG-1-deficient Mice

An imbalanced immune system has long been known to influence a variety of mood disorders including anxiety, obsessive-compulsive disorders and depression. In this study, we sought to model the impact of an immunocompromised state on these emotional behaviors using RAG-1⁻/⁻ mice, which lack T and B cells. We also investigated the relative contribution of CD4⁺ or CD8⁺ T cells to these manifestations using RAG-1⁻/⁻/OT-II and RAG-1⁻/⁻/OT-I transgenic mice, respectively. Our results show that RAG-1⁻/⁻ mice present a significant increase in digging and marble-burying activities compared with wild-type mice. Surprisingly, these anxiety-like behaviors were significantly reverted in RAG-1⁻/⁻/OT-II but not RAG-1⁻/⁻/OT-I transgenic mice. Immunodepletion experiments with anti-CD4 or anti-CD8 in C57/BL6 mice or repopulation studies in RAG-1⁻/⁻ mice did not reproduce these findings. Microarray analysis of the brain of RAG-1⁻/⁻ and RAG-1⁻/⁻/OT-II mice revealed a significantly different gene fingerprint, with the latter being more similar to wild-type mice than the former. Further analysis revealed nine main signaling pathways as being significantly modulated in RAG-1⁻/⁻ compared with wild-type mice. Taken together, these results suggest that life-long rather than transient immunodeficient conditions influence the emotional behaviors in mice. Most interestingly, these effects seem to correlate with a specific absence of CD4⁺ rather than CD8⁺ T cells. Validation of these findings in man might provide new clues on the mechanism by which early life immune modulation might impact mood response in adults and provide a further link between immune and emotional well-being.