Bond lifetime under force as a potential mechanism underlying the pathogenicity of low affinity CD8 T cells in experimental cerebral malaria 3182

Abstract Description Despite the presence of anti-malarial treatments, cerebral malaria persists as one of the most lethal malaria complications. CD8 T cells mediate the development of experimental cerebral malaria (ECM), which is characterized by breakdown of the blood-brain barrier (BBB). During a Plasmodium infection, CD8 T cells recognize different Plasmodium epitopes and expand, leading to polyclonal populations with T cell receptors (TCRs) of different reactivity and affinity. Generally, T cells harboring high affinity TCRs are believed to dominate any polyclonal T cell response and to be the most potent cells during an immune response. We have made the paradigm-shifting discovery that pathogenicPlasmodium-reactive CD8 T cells with low affinity TCRs dominate the CD8 T cell response during ECM. In adoptive transfer experiments, high affinity CD8 T cells are unable to drive BBB dysfunction to the same extent as low affinity cells. We have found that high and low affinity Plasmodium-reactive CD8 T cells display different phenotypes. High affinity CD8 T cells might be dysfunctional or undergoing apoptosis, consistent with their inability to mediate BBB breakdown. TCR affinity can impact functional outcome by inducing a different bond lifetime under force. We have identified TCRs specific for the Plasmodium GAP50 epitope and transfected these TCRs into 58TCR-ve cells. High affinity GAP50-specific TCRs induced longer bond lifetimes under force compared to low affinity GAP50-specific TCRs. Funding Sources NIH 5R01AI167422-04 Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)