The Contribution of Co-signaling Pathways to Anti-malarial T Cell Immunity

Abstract

Plasmodium spp., the causative agent of malaria, caused 212 million infections in 2016 with 445,000 deaths, mostly in children. Adults acquire enough immunity to prevent clinical symptoms but never develop sterile immunity. The only vaccine for malaria, RTS,S, shows promising protection of a limited duration against clinical malaria in infants but no significant protection against severe disease. There is now abundant evidence that T cell functions are inhibited during malaria, which may explain why vaccine are not efficacious. Studies have now clearly shown that T cell immunity against malaria is subdued by multiple the immune regulatory receptors, in particular, by programmed cell-death-1 (PD-1). Given there is an urgent need for an efficacious malarial treatment, compounded with growing drug resistance, a better understanding of malarial immunity is essential. This review will examine molecular signals that affect T cell-mediated immunity against malaria.

A Peptide-Based PD1 Antagonist Enhances T-Cell Priming and Efficacy of a Prophylactic Malaria Vaccine and Promotes Survival in a Lethal Malaria Model

“…However, the potential side effects associated with the current mAb-based immune checkpoint cancer treatments, as well as the potential exacerbation of cerebral malaria, have impeded attempts to progress checkpoint inhibitors for use in malaria (29). Nevertheless, with the spread of drug resistance, the absence of a truly efficacious vaccine, and the promise of alternatives such as soluble PD-L2 that can generate long-term protection with a reduced incidence of cerebral malaria (30), new modalities that can be safely adopted for infectious disease vaccines and therapeutics require investigation.…”

Immunosuppression in Malaria: Do Plasmodium falciparum Parasites Hijack the Host?

“…Chronic (or repetitive) exposure to malaria is reflected on T cells as long-lasting perturbations known as "exhaustion markers", such as the aforementioned TNFR2 [96]. Over the last decade, the understanding of key steps in the regulation of T cell responses has led to the discovery of what has been named as "immune checkpoints" [97].…”

“…Over the last decade, the understanding of key steps in the regulation of T cell responses has led to the discovery of what has been named as "immune checkpoints" [97]. These, known in malaria as "exhaustion markers", are surface proteins in malaria pathogenesis that play a role in immune mechanisms to promote or impede protection through co-stimulatory or co-inhibitory receptors, respectively [96]. The expression of "exhaustion markers" on CD4 + cells, together with the presence of Tregs and anti-inflammatory cytokine production, are long lasting effects in children even after cure, which may contribute to a prolonged state of immunosuppression until the next infection [98].…”

“…The expression of "exhaustion markers" on CD4 + cells, together with the presence of Tregs and anti-inflammatory cytokine production, are long lasting effects in children even after cure, which may contribute to a prolonged state of immunosuppression until the next infection [98]. These "immune checkpoint" pathways controlling tolerance and tissue collateral damage during malaria infections have recently been reviewed elsewhere [96].…”

Expansion of Functional Myeloid-Derived Suppressor Cells in Controlled Human Malaria Infection

“…To date, CD4 + regulatory T cells (T reg ) have been the main focus of studies to investigate the mechanism of immunological tolerance by immunosuppression during malaria (33)(34)(35)(36)(37)(38). T reg block T cell responses by inhibitory cytokines (membranebound or pericellular), cytolysis, cellular metabolic disruption and modulating dendritic cells through co-stimulatory markers (39)(40)(41)(42). Interestingly, dendritic cells may also contribute to immunosuppression (43)(44)(45).…”