γδ T Cells Contribute to Injury in the Developing Brain

Brain injury in premature infants, especially periventricular leukomalacia, is an important cause of neurologic disabilities. Inflammation contributes to perinatal brain injury development, but the essential mediators that lead to early-life brain injury remain largely unknown. Neonates have reduced capacity for mounting conventional alpha beta T-cell responses. However, gamma delta T cells are already functionally competent during early development and are important in early-life immunity. We investigated the potential contribution of gamma delta T cells to preterm brain injury using postmortem brains from human preterm infants with periventricular leukomalacia and two animal models of preterm brain injury the hypoxic-ischemic mouse model and a fetal sheep asphyxia model. Large numbers of gamma delta T cells were observed in the brains of mice, sheep, and postmortem preterm infants after injury, and depletion of gamma delta T cells provided protection in the mouse model. The common gamma delta T-cell-cell-cell associated cytokines interferon-gamma and IL-17A were not detectable in the brain. Although there were increased mRNA levels of Il17f and Il22 in the mouse brains after injury, neither IL-17F nor IL-22 cytokines contributed to preterm brain injury. These findings highlight unique features of injury in the developing brain, where, unlike injury in the mature brain, gamma delta T cells function as initiators of injury independently of common gamma delta T-cell associated cytokines. This finding will help to identify therapeutic targets for preventing or treating preterm infants with brain injury.