[Research Articles] Necrotizing enterocolitis induces T lymphocyte-mediated injury in the developing mammalian brain

Necrotizing enterocolitis (NEC) causes acute intestinal necrosis in premature infants and is associated with severe neurological impairment. In NEC, Toll-like receptor 4 is activated in the intestinal epithelium, and NEC-associated brain injury is characterized by microglial activation and white matter loss through mechanisms that remain unclear. We now show that the brains of mice and humans with NEC contained CD4+ T lymphocytes that were required for the development of brain injury. Inhibition of T lymphocyte influx into the brains of neonatal mice with NEC reduced inflammation and prevented myelin loss. Adoptive intracerebroventricular delivery of gut T lymphocytes from mice with NEC into Rag1–/– recipient mice lacking CD4+ T cells resulted in brain injury. Brain organoids derived from mice with or without NEC and from human neuronal progenitor cells revealed that IFN- release by CD4+ T lymphocytes induced microglial activation and myelin loss in the organoids. IFN- knockdown in CD4+ T cells derived from mice with NEC abrogated the induction of NEC-associated brain injury after adoptive transfer to naïve Rag1–/– recipient mice. T cell receptor sequencing revealed that NEC mouse brain-derived T lymphocytes shared homology with gut T lymphocytes from NEC mice. Intraperitoneal injection of NEC gut-derived CD4+ T lymphocytes into naïve Rag1–/– recipient mice induced brain injury, suggesting that gut-derived T lymphocytes coul...

Source: Science Translational Medicine - January 6, 2021 Category: Biomedical Science Authors: Zhou, Q., Nino, D. F., Yamaguchi, Y., Wang, S., Fulton, W. B., Jia, H., Lu, P., Prindle, T., Pamies, D., Morris, M., Chen, L. L., Sodhi, C. P., Hackam, D. J. Tags: Research Articles Source Type: research