Malaria-Specific and Nonspecific Activation of CD8+ T Cells during Blood Stage of Plasmodium berghei Infection

Abstract

Cerebral malaria is one of the severe complications of Plasmodium falciparum infection. Studies using a rodent model of Plasmodium berghei ANKA infection established that CD8+ T cells are involved in the pathogenesis of cerebral malaria. However, it is unclear whether and how Plasmodium-specific CD8+ T cells can be activated during the erythrocyte stage of malaria infection. We generated recombinant Plasmodium berghei ANKA expressing OVA (OVA-PbA) to investigate the parasite-specific T cell responses during malaria infection. Using this model system, we demonstrate two types of CD8+ T cell activations during the infection with malaria parasite. Ag (OVA)-specific CD8+ T cells were activated by TAP-dependent cross-presentation during infection with OVA-PbA leading to their expression of an activation phenotype and granzyme B and the development to functional CTL. These highly activated CD8+ T cells were preferentially sequestered in the brain, although it was unclear whether these cells were involved in the pathogenesis of cerebral malaria. Activation of OVA-specific CD8+ T cells in RAG2 knockout TCR-transgenic mice during infection with OVA-PbA did not have a protective role but rather was pathogenic to the host as shown by their higher parasitemia and earlier death when compared with RAG2 knockout mice. The OVA-specific CD8+ T cells, however, were also activated during infection with wild-type parasites in an Ag-nonspecific manner, although the levels of activation were much lower. This nonspecific activation occurred in a TAP-independent manner, appeared to require NK cells, and was not by itself pathogenic to the host.

Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease

“…1) : depletion of CD8 + T cells either early (from start of infection) or late (from day 4 or 5 post-infection) in infection completely inhibits the development of ECM (Yanez et al 1996 ;Belnoue et al 2002 ;Hermsen et al 1997). CD8 + T cells migrate to the brain in a largely antigen-specific manner, following cross-presentation of malaria antigens by classical CD8 + dendritic cells (deWalick et al 2007 ;Lundie et al 2008 ;Miyakoda et al 2008). The recent demonstration that NK cell-derived IFN-c is required for upregulation of CXCR3 on CD8 + T cells and for their subsequent migration to and accumulation within the brain ) is consistent with the observation that IFN-cR signalling regulates sequestration of CD8 + T cells within the brain in susceptible mice (Belnoue et al 2008), and reveals important interactions between innate and adaptive immune responses in the pathogenesis of ECM, opening up potential new avenues of research into the role of innate immune responses, and of genetic variation in innate response genes, in the pathogenesis of human CM.…”

Phenotypic and functional profiling of malaria-induced CD8 and CD4 T cells during blood-stage infection with Plasmodium yoelii

“…Very recently, a few groups demonstrated the expansion of CD4 and CD8 T cells during the blood stage of malaria, but these studies did not address the expression, stability and fidelity of the above-mentioned markers during infection. 12,30,31 The purpose of this study was to evaluate the extent, quality and quantity of CD8 and CD4 T-cell activation after blood-stage malaria infection that did not involve a liver stage. We found that both CD8 and CD4 T cells These data clearly demonstrate that CD8 and CD4 T cells are activated following an acute blood-stage malaria infection.…”

Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

“…The lack of TCR transgenic mouse lines specific for Plasmodium Ags led to the generation of transgenic malaria parasites expressing model Ags, such as PbTG and OVA-Plasmodium berghei ANKA (PbA) (2,4,9,10), for which widely used murine T cell lines such as OT-I and OT-II could be used to monitor specific T cell responses. Although the use of these parasites in conjunction with model T cell lines has aided the study of antimalarial CD4 + and CD8 + T cell responses (6,(11)(12)(13)(14)(15), wild-type (WT) parasites and transgenic T cells capable of recognizing authentic parasitederived Ags are preferred, as they more closely resemble endogenous responses to natural infections.…”