Activated Peripheral CD8 + T Lymphocytes Inhibit the Proliferation of Hippocampal Neural Stem Cells via the IFN-γ/JAK/STAT Signaling Pathway

Background: The inhibition of hippocampal neurogenesis is associated with cognitive impairment in a variety of diseases, which are often accompanied by neuroinflammation. Our preliminary results revealed that the number of CD8 + T lymphocytes infiltrating the hippocampus of mice that underwent major abdominal surgery increased significantly and contributed to the inhibition of hippocampal neurogenesis and cognitive impairment. However, which stage of hippocampal neurogenesis is affected and the specific mechanisms involved remain unclear.

Methods: We isolated hippocampal neural stem cells (NSCs) and peripheral CD8 + T lymphocytes from C57BL/6 mice and then used a transwell coculture system to mimic the state in which peripheral CD8 + T lymphocytes infiltrated the parenchyma but did not directly contact NSCs.

Results: The results showed that activated peripheral CD8 + T lymphocytes inhibited the proliferation of NSCs in a time- and dose-dependent manner. The inhibitory effect of CD8 + T lymphocytes on NSC proliferation may be achieved through the secretion of cytokines, especially IFN-γ, as administration of IFN-γ neutralizing antibodies could attenuate this effect. Adding IFN-γ directly to the coculture system also inhibited NSC proliferation, even without activating T cells. Additionally, the JAK2/STAT1 pathway in NSCs was activated by activated peripheral CD8 + T lymphocytes or exogenous IFN-γ, and a JAK2-specific inhibitor reversed the inhibitory effect of activated peripheral CD8 + T lymphocytes on NSC proliferation.

Conclusion: These results demonstrated that activated peripheral CD8 + T lymphocytes can indirectly inhibit the proliferation of hippocampal NSCs by secreting IFN-γ and subsequently activating the JAK/STAT signaling pathway in NSCs. Our study may help to better elucidate the regulatory role of neuroinflammation in hippocampal neurogenesis, especially in some pathological states.

CD8 + T lymphocytes; IFN‐γ; JAK/STAT; neural stem cells; proliferation.