Cytokines are proteins secreted in the central nervous system by neurons, microglia, and astrocytes, as well as infiltrating peripheral immune cells, under both physiological and pathological conditions. While the expression of cytokines and their receptors in the brain by neurons, microglia, and astrocytes, and their impact on structural changes at the synaptic level, have been extensively studied, recent advances have revealed the presence of peripheral immune cells in the brain and its borders, including the meninges, choroid plexus, and skull bone marrow, even under steady conditions. These immune cells are suggested to play a physiologically beneficial role by secreting cytokines that influence brain plasticity, social behavior, and learning and memory. CD8+ T cells, known for their formidable role in the adaptive immune system against viral infections, have traditionally been recognized primarily for host defense. However, recent breakthroughs have shed light on an unexpected dimension of CD8+ T cell engagement in the brain, even in non-pathological conditions. This study unveils a novel facet of CD8+ T cell biology, demonstrating their entry into the brain in the early stages of life and subsequent clonal expansion facilitated by interactions with microglia. Through the use of CD8 knockout and depletion paradigms, we discern their impact on sophisticated executive behaviors, including sociability, emotionality, and cognition. Additionally, our findings reveal increased neural activities and an altered excitatory/inhibitory ratio in neurons of the prefrontal cortex in the absence of CD8+ T cells. These findings not only illuminate the multifaceted role of CD8+ T cells but also provide insights into their involvement in brain homeostasis, thereby expanding our comprehension of the intricate interplay orchestrating the brain’s dynamic environment.
