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CD8 T cells induce cerebral malaria through antigen-dependent interactions with brain vascular endothelial cells

Thursday, September 17, 2015 — Poster Session III

3:30 p.m. – 5:00 p.m.
FAES Terrace
NINDS
IMMUNO-32

* FARE Award Winner

Authors

  • PA Swanson II
  • GT Hart
  • LH Miller
  • SK Pierce
  • DB McGavern

Abstract

Cerebral malaria is a fatal neurological condition arising from infection by the protozoan parasite Plasmodium falciparum. Because the mechanisms that lead to cerebral malaria are unknown, we investigated the cause of this disease using a murine model of experimental cerebral malaria (ECM). We observed a large influx of immune cells into the brain during ECM, however only depletion of CD8 T cells completely prevented breakdown of CNS vasculature and rescued mice from death. To understand how CD8+ T cells induced this disease, we adoptively transferred Pb-specific CD8+ T cells into mice and used two-photon microscopy (TPM) to track their location and motility in the brain. Interestingly, Pb-specific CD8 T cells were primarily observed crawling along or arresting on the lumen of cerebral blood vessels during the development of ECM. We also found increased expression of antigen presentation and adhesion molecules on brain endothelial cells during ECM, which was associated with the observed CD8 T cell behavior. Because cerebral endothelial cells can acquire parasite antigen, we hypothesized that the interactions between CD8+ T cells and endothelial cells were antigen-specific. To address this theory, we demonstrated by TPM that Pb-specific CD8+ T cells spent significantly more time arrested along brain vasculature than activated non-specific CD8+ T cells. In addition, we generated bone marrow chimeras lacking antigen-presenting machinery on endothelial cells. The absence of antigen presentation by endothelial cells reduced Pb-specific CD8+ T cell arrest and prevented ECM. These data indicate CD8+ T cells drive ECM through antigen-dependent interactions with cerebral blood vessels.

Category: Immunology