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T cell-mediated immunity to malaria

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Abstract

Immunity to malaria has been linked to the availability and function of helper CD4+ T cells, cytotoxic CD8+ T cells and γδ T cells that can respond to both the asymptomatic liver stage and the symptomatic blood stage of Plasmodium sp. infection. These T cell responses are also thought to be modulated by regulatory T cells. However, the precise mechanisms governing the development and function of Plasmodium-specific T cells and their capacity to form tissue-resident and long-lived memory populations are less well understood. The field has arrived at a point where the push for vaccines that exploit T cell-mediated immunity to malaria has made it imperative to define and reconcile the mechanisms that regulate the development and functions of Plasmodium-specific T cells. Here, we review our current understanding of the mechanisms by which T cell subsets orchestrate host resistance to Plasmodium infection on the basis of observational and mechanistic studies in humans, non-human primates and rodent models. We also examine the potential of new experimental strategies and human infection systems to inform a new generation of approaches to harness T cell responses against malaria.

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Acknowledgements

The authors apologize to the countless researchers whose contributions are not discussed in this manuscript owing to space limitations. They also thank the Butler and Harty laboratory members for helpful discussions. Work in the laboratory of N.S.B. is supported by grants from the US National Institutes of Health (NIH) (AI125446 and AI127481). Work in the laboratory of J.T.H. is supported by grants from the NIH (AI42767, AI95178, AI100527 and AI114543).

Reviewer information

Nature Reviews Immunology thanks A. Haque, M. Good and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

All authors contributed to the discussion of content and to the writing and the editing of the manuscript.

Competing interests

The authors declare no competing interests.

Correspondence to John T. Harty.

Glossary

Sporozoite

A Plasmodium parasite life form transmitted by mosquito bite and capable of initiating the asexual cycle of growth and differentiation in the vertebrate host.

Merozoites

Plasmodium parasite life forms that first develop in infected hepatocytes and are capable of initiating either sexual or asexual cycles of development in host red blood cells.

Merosome

Host cell-derived, membrane-bound structure containing multiple merozoites that buds from infected hepatocytes during Plasmodium egress from the liver. Merosomes release merozoites into circulation after rupture.

RTS,S

The candidate anti-malarial vaccine furthest along in global development. RTS,S comprises two subdomains of the Plasmodium falciparum circumsporozoite protein (CSP) that are associated with units of the hepatitis B surface antigen and formulated with the adjuvant AS01 (3-O-desacyl-4′-monophosphoryl lipid A and the saponin QS-21). Infection is prevented by inducing antibodies that either immobilize sporozoites in the skin or prevent sporozoites from infecting the liver.

Circumsporozoite protein

(CSP). Immunodominant, high-density surface antigen expressed by Plasmodium sporozoites that is the target of humoral and cellular immune responses that either block sporozoite infection of the liver or eliminate infected hepatocytes, respectively.

Chemoprophylaxis and sporozoite (CPS) immunization

A vaccination strategy whereby virulent sporozoites are delivered by either mosquito bites or needle injection with prophylactic delivery of a drug targeting Plasmodium blood stages. Parasites initiate and complete liver-stage development, release merozoites and initiate the first wave of blood-stage infection before being eliminated by the drug. Vaccinated individuals are thereby exposed to antigens that derive from multiple parasite life cycle stages while remaining protected against clinical disease by the anti-blood-stage drug.

Apicoplasts

Non-photosynthetic organelles that characterize protists within the phylum Apicomplexa and are likely derived from an algal endosymbiont. All apicoplast functions are not fully known, but defined activities primarily relate to essential metabolic pathways necessary for the viability of Plasmodium and other apicomplexans.

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Fig. 1: Plasmodium life cycle.
Fig. 2: Overview of tissue-specific, T cell-mediated immune resistance networks during Plasmodium infection.