Neuronal Influence on T-Cell Exhaustion: The Role of TGF-β Pathways in Immune Regulation

초록

The concept of CNS immune privilege is being revisited based on the discovery of classical lymphatic vessels in the meninges of the CNS, which provide immune surveillance of the CNS. Many studies have focused on the trafficking of immune cells into the CNS; however, fewer studies have focused on neuron-immune interactions. The way neurons regulate T-cell activation has not been thoroughly studied. This study investigated how neurons regulate T-cell activation using a neuron-lymphocyte co-culture system in vitro. Primary cortical neurons were isolated from fetal brains at 13-14 days of gestation and cultured for one week. Lymphocytes were isolated from the spleen and lymph nodes and co-cultured with neurons in the presence of anti-CD3/CD28 antibodies. Subsequently, T-cell activations were observed. Interestingly, effector cytokines such as IFN-?, IL-4, IL-17A, IL-6, and IL-13 were decreased by neurons, while CD44hi CD62Llo effector phenotype T cells were increased. Neurons significantly impact CD8 T cells, showing increased PD-1, Tim-3, and CD73 expressions and decreased Granzyme B expression. Intriguingly, SB431542, a TGF-?-pathway inhibitor, restored these phenotypes. Our research underscores the significant role of neurons in inducing exhausted T-cell phenotypes, and these immunosuppressive functions of neurons may be mediated by TGF-? pathways. This critical insight into the role of TGF-? pathways in neuron-mediated T-cell suppression could potentially explain the meaning of CNS immune privilege. These findings may be paramount for future research and therapeutic development, particularly in brain diseases or cancer.