CD8 ⁺ T cells are essential for the effects of enriched environment on hippocampus-dependent behavior, hippocampal neurogenesis and synaptic plasticity

Enriched environment (EE) induces plasticity changes in the brain. Recently, CD4 ⁺ T cells have been shown to be involved in brain plasticity processes. Here, we show that CD8 ⁺ T cells are required for EE-induced brain plasticity in mice, as revealed by measurements of hippocampal volume, neurogenesis in the DG of the hippocampus, spinogenesis and glutamatergic synaptic function in the CA of the hippocampus. As a consequence, EE-induced behavioral benefits depend, at least in part, on CD8 ⁺ T cells. In addition, we show that spleen CD8 ⁺ T cells from mice housed in standard environment (SE) and EE have different properties in terms of 1) TNFα release after in vitro CD3/CD28 or PMA/Iono stimulation 2) in vitro proliferation properties 3) CD8 ⁺ CD44 ⁺ CD62L ^low and CD62L ^hi T cells repartition 4) transcriptomic signature as revealed by RNA sequencing. CD8 ⁺ T cells purified from the choroid plexus of SE and EE mice also exhibit different transcriptomic profiles as highlighted by single-cell mRNA sequencing. We show that CD8 ⁺ T cells are essential mediators of beneficial EE effects on brain plasticity and cognition. Additionally, we propose that EE differentially primes CD8 ⁺ T cells leading to behavioral improvement.