Cortical Neurons Induce Both CD103+ Tissue-Resident Memory and CD73+ Exhausted CD8+ T Cell Phenotypes to Suppress Inflammatory Responses

초록

Background The brain is recognized as an immune-privileged organ where adaptive immunity and inflammation are tightly regulated. However, when the brain sustains damage, various immune cells infiltrate, leading to neuronal cell death, with T cells playing a crucial role in brain inflammation. Aim We established an in vitro co-culture system of neurons and T cells to elucidate how neurons regulate T cell activity. Method Cortical neurons were isolated from the embryos of male C57BL/6 mice and cultured in neuronal culture media. After 7 days, the neurons were co-cultured with T cells under anti-CD3/CD28 stimulation. The surface markers of T cells were measured using flow cytometry, and cytokine production was assessed by ELISA. Additionally, CD8 T cells were isolated, and several gene expressions were quantified using qRT-PCR. Result Neurons induced CD44+ CD62Llo effector T cell phenotypes under anti-CD3/CD28 stimulation but suppressed T cell cytokine expression. Additionally, neurons increased the expression of PD-1, a marker of exhausted T cells, and CD73, while decreasing Granzyme B expression, which is associated with cytotoxic T cell activation. Furthermore, neurons induced the expression of CD103+, CCR9, and Hic, which are known to be involved in tissue-resident memory T cells (Trm). Interestingly, the expression of these proteins was fully restored in the presence of SB431542, a TGF-β pathway inhibitor. Our findings demonstrate that neurons suppress inflammatory responses by inducing CD103+ Trm and CD73+ exhausted CD8+ T cells through the TGF-β pathway. Conclusions This study enhances our understanding of the immunoregulatory functions of neurons and suggests the potential for developing new therapeutic strategies for the treatment and prevention of brain inflammatory diseases.