Breakdown of the blood brain barrier in Experimental Cerebral Malaria is caused by CD8+ T cells with low affinity TCRs

Abstract

Abstract Malaria is a worldwide health concern killing over 400,000 people each year, many of them children under 5 years old. One severe outcome of Plasmodium infection is cerebral malaria caused by a dysregulation of the immune response in the central nervous system. Using an established mouse model of cerebral malaria called experimental cerebral malaria(ECM) using Plasmodium berghei ANKA (PbA) infections of C57BL/6J mice have shown that breakdown of the blood brain barrier is mediated by IFN-g producing CD8 T cells. Here, using novel techniques to determine the affinity of the MHC:peptide:TCR interaction we have discovered that although there are high affinity cells in the population trafficking to the CNS, surprisingly a large majority of these PbA-reactive pathogenic CD8 T cells have low affinity TCRs, and a large percentage of them cannot be detected by tetramer. Importantly we show that these low affinity cells are also producing IFN-g suggesting they are pathogenic. Through adoptive transfer experiments we show that high and low affinity T cells remain stable in their affinity profile. Furthermore we show here that low affinity cells are needed for breakdown of the blood brain barrier – CD8 T cells bearing high affinity TCRs for the GAP50 peptide of Plasmodium have an impaired ability to cause ECM compared to low affinity CD8 T cells. This work demonstrates that low affinity cells are the major component of the immunopathology causing ECM when infected with PbA and contrasts with current dogma which suggests that high affinity cells are the main cells responding in these types if infections. Supported by grants from NIH (R01 AI167422)