The adoptive transfer of BCG-induced T lymphocytes contributes to hippocampal cell proliferation and tempers anxiety-like behavior in immune deficient mice

Abstract

We previously have reported that neonatal Bacillus Calmette-Guerin (BCG) vaccination improves neurogenesis and behavior in early life through affecting the neuroimmune milieu in the brain, but it is uncertain whether activation phenotypes and functional changes in T lymphocytes shape brain development. Here, we studied the effects of BCG vaccination via the adoptive transfer of T lymphocytes from the BALB/c wild-type mice into naive mice. Our results show that mice adoptive BCG-induced lymphocytes (BCG->naive mice) showed anxiolytic and antidepressant-like performance when completing an elevated plus maze (EPM) test. Meanwhile, BCG->naive mice possess more cell proliferation and newborn neurons than PBS->naive and nude mice in the hippocampus. IFN-γ and IL-4 levels in the serum of BCG- >naive mice also increased, while TNF-α and IL-1β levels were reduced relative to those of PBS->naive and nude mice. We further found that BCG->naive mice showed different repartition of CD4+ and CD8+ T cell to naive (CD62L+CD44low), effector memory (CD62L-CD44hi), central memory (CD62L+CD44hi) and acute/activated effector (CD62L-CD44low) cells in the spleen. Importantly, the adoptive transfer of BCG-induced T lymphocytes infiltrated into the dura mater and brain parenchyma of the nude mice. Activation phenotypes and functional changes in T lymphocytes are very likely to affect the neuroimmune milieu in the brain, and alterations in ratios of splenic CD4+ and CD8+ memory T cells may affect the expression of correlative cytokines in the serum, accounting for our behavioral results. We conclude thus that the adoptive transfer of BCG-induced T lymphocytes contributes to hippocampal cell proliferation and tempers anxiety-like behavior in immune deficient mice. Our work shows that BCG vaccination improves hippocampal cell proliferation outcomes and behaviors, likely as a result of splenic effector/memory T lymphocytes regulating the neuroimmune niche in the brain.