Reduced perforin release from T cells as a mechanism underlying hypothermia‐mediated neuroprotection

Abstract

Objective The underlying mechanisms of therapeutic hypothermia, which protects neurons after severe brain damage, are partially understood. T cells infiltrate the brain within days after cerebral ischemia and play essential roles in exacerbating the delayed phase of brain injury by producing cytotoxic factors, which were also systematically shown to be involved in brain damage. Periphery brain abnormalities are interesting, because the periphery might constitute a pathway to the central nervous system and therefore could also be a target of therapeutic hypothermia. We elucidated the effects of hypothermia and hyperthermia on peripheral T cell-derived perforin (Pfn), and the underlying mechanism of Pfn-mediated neurotoxicity and death of brain microvascular endothelial cells (BMVECs). Methods We determined the levels of Pfn produced by activated CD4 + and CD8 + T cells obtained from healthy humans under hypothermic, normothermic and hyperthermic conditions. The viability in response to Pfn treatment was assessed in neuronal Neuro-2a and brain microvascular endothelial bEnd.3 cells.Results Compared with normothermia, Pfn release in both CD4 + and CD8 + T cells was reduced by hypothermia, but augmented by hyperthermia. Pfn caused the death of Neuro-2a cells, and induced both apoptosis and necrosis in bEnd.3 cells; both effects were concentration-dependent.Conclusions Hypothermia reduces T cell-derived release of Pfn, which mediates neuronal cell death and apoptosis/necrosis of BMVECs, suggesting that therapeutic hypothermia elicits protection in the neurons and BMVECs in the delayed phase of brain injury by directly reducing the release of T cell-derived Pfn. BMVECs protection can aid in reduced vascular permeability and blood-brain barrier protection.

Cold working environments as an occupational risk factor for COVID-19

“…Indeed, the immune profile of patients with severe COVID-19 admitted to intensive care compared to non-intensive care patients demonstrates significantly reduced perforin expression [ 12 ]. In vitro studies using incubated human lymphocytes found that compared to normal body temperature (37°C), perforin expression by CD4 + and CD8 + T cells was significantly reduced at temperatures of 33°C by over 50% and 35%, respectively, but, interestingly, raised at the modestly higher temperature of 39°C [ 13 ]. Similar in vitro effects of temperature have been described for the expression of Fas ligand [ 14 ].…”