Low affinity CD8 T cells dominate experimental cerebral malaria resulting from Plasmodium infection

Abstract

Abstract Due to its impact on global health, gaining insight into the immune mechanisms that control Plasmodium infections and specifically the complications associated with cerebral malaria are key for developing appropriate therapeutics. For Plasmodium berghei ANKA infections of C57BL/6 mice, activated CD8 T cells mediate the development of symptoms resembling cerebral malaria (experimental cerebral malaria; ECM). We utilized the sensitivity of the two dimensional (2D) micropipette adhesion frequency assay to define the affinity and frequency of immunodominant glideosome associated protein 50 (GAP50)40-48 epitope in spleen and brain of P. berghei infected mice. Compared to tetramer staining of the spleen on day 5, which shows approximately 1.2% of the CD8 cells are antigen specific, the micropipette assay showed that nearly 30% of the CD8 T cells were specific for GAP5040-48. These differences in frequency are due to the fact the micropipette detects both high and low affinity populations of GAP50 specific cells, whereas tetramers are generally limited to detecting higher affinity cells. In P. berghei ANKA infection low affinity CD8 T cells migrate to the brain in large numbers indicating that they are important components of the pathogenic response. Adoptive transfer experiments with P14 transgenic T cells specific for the GP33 epitope of LCMV show that only Plasmodium-reactive cells migrate to the brain during infection providing further evidence that the low affinity CD8 T cells in the brain are Plasmodium-reactive. Taken together, these results demonstrate for the first time that both low and high affinity CD8 T cells participate in the polyclonal CD8 T cell response to Plasmodium infection.