Abstract
CD8+ T cells are key players during infection with the malaria parasite Plasmodium berghei ANKA (PbA). While they cannot provide protection against blood-stage parasites, they can cause immunopathology, thus leading to the severe manifestation of cerebral malaria. Hence, the tight control of CD8+ T cell function is key in order to prevent fatal outcomes. One major mechanism to control CD8+ T cell activation, proliferation and effector function is the integration of co-inhibitory and co-stimulatory signals. In this study, we show that one such pathway, the HVEM-CD160 axis, significantly impacts CD8+ T cell regulation and thereby the incidence of cerebral malaria. Here, we show that the co-stimulatory molecule HVEM is indeed required to maintain CD8+ T effector populations during infection. Additionally, by generating a CD160−/− mouse line, we observe that the HVEM ligand CD160 counterbalances stimulatory signals in highly activated and cytotoxic CD8+ T effector cells, thereby restricting immunopathology. Importantly, CD160 is also induced on cytotoxic CD8+ T cells during acute Plasmodium falciparum malaria in humans. In conclusion, CD160 is specifically expressed on highly activated CD8+ T effector cells that are harmful during the blood-stage of malaria.
Highlights
The inflammatory response to blood-stage malaria is characterized by a strong Th1 polarization and T cell induced immunopathology
We analyzed the proliferative capacity, and the persistence of CD8+ T cells during an acute P. berghei ANKA (PbA) infection by a competitive, adoptive T cell transfer assay in which wild type (WT) OT-1 and HVEM−/− OT-1 CD8+ T cells, labeled with different proliferation dyes, were mixed in equal proportions and transferred into WT hosts
We found that CD8+CD28+GzmB+ T cells were enriched in malaria patients compared to healthy controls and patients suffering from autoimmune hepatitis (AIH), primary billary cholangitis (PBC), primary sclerosing cholangitis (PSC) or chronic hepatitis B virus (HBV) infection (Figure 6A)
Summary
The inflammatory response to blood-stage malaria is characterized by a strong Th1 polarization and T cell induced immunopathology. Plasmodial antigens can be cross-presented on activated brain endothelial cells [1] leading to the release of cytotoxic molecules and pro-inflammatory cytokines such as granzymes and IFNγ by T cells [2,3,4,5] This leads to the severe manifestation of experimental cerebral malaria (ECM) [5]. We have shown and so have others that the co-inhibitory receptors PD-1, CTLA4 and BTLA are induced during malaria These co-inhibitory receptors play an important role in the regulation of CD4+ T cell activation controlling immunopathology during the blood-stage [6,7,8,9,10,11]. The control of CD8+ T cells during the blood-stage of the infection
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