T cell-mediated immunity to malaria

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.

FIGURE 1:. Plasmodium life cycle.

The life cycle begins when a Plasmodium-infected female Anopheles mosquito takes a blood meal from a human host and deposits Plasmodium sporozoites into the skin. Motile sporozoites exit the dermis and travel through the blood to access hepatocytes. Sporozoites invade liver cells via interactions between Plasmodium circumsporozoite protein (CSP) and heparin sulfate molecules expressed on hepatocytes. One P. falciparum sporozoite will undergo differentiation over 6–7 days and amplify into ~10,000 merozoites. Infected hepatocytes release merozoites and merosomes, which are membrane bound packets of merozoites, into the blood stream where they proceed to invade erythrocytes. Merozoites undergo repeated rounds of asexual replication. A minor proportion of merozoites will differentiate into either male or female gametocytes that can be ingested by other female Anopheles mosquitos. In the mosquito midgut, male and female gametocytes fuse and develop into a motile ookinete. Ookinetes embed within the mosquito midgut wall and develop further into oocysts. Each oocyst produces thousands of sporozoites over a period of two weeks. Sporozoites eventually migrate to the salivary glands and poise the mosquito to transmit malaria to a new host.

FIGURE 2:. Overview of tissue-specific, T cell-mediated immune resistance networks during Plasmodium infection.

CD8α⁺ dendritic cells (DC) in the skin-draining lymph nodes and spleen, as well as CFS1R⁺ CD11c⁺ cells in the liver-draining lymph nodes, serve as antigen presenting cells and play an important role in bridging innate and adaptive immune responses during malaria. Upon phagocytosis of merozoites, parasitized RBC (pRBC), sporozoites, debris from infected hepatocytes, or circumsporozoite protein formulated as part of the RTS,S vaccine, DCs will process and present Plasmodium antigens to activate naïve CD4⁺ and CD8⁺ T cells. DC production of specific cytokines, such as IL-12 and IL-6, skew CD4⁺ T cell differentiation toward T helper 1 (Th1) and T follicular helper (Tfh) lineages. Th1 cells produce the cytokine IFN-γ that activates macrophages to enhance their phagocytic function and stimulates production of reactive oxygen species that are toxic to the parasite. Tfh cells engage parasite-specific B cells and orchestrate the germinal centre (GC) reaction, where they express co-stimulatory factors (CD40L) and secreted soluble factors (IL-4 and IL-21) that promote GC B cell (GCB) antibody isotype switching, affinity maturation, and somatic hypermutation, as well as the generation of memory B cells (MBC) and long-lived antibody-secreting plasma cells (PC). Parasite-specific antibodies potentially function to immobilize or target sporozoites for antibody dependent cellular cytotoxicity (ADCC), block merozoite invasion of RBCs, opsonize pRBC to enhance their phagocytosis, target merozoites and pRBC for ADCC, and activate the classical complement-pathway. Sporozoite- or liver-stage-specific, tissue-resident (Trm) CD8⁺ T cells elaborate the cytokines IFN-γ and TNF and trigger extrinsic cell death pathways via expression of perforin and granzyme to kill infected hepatocytes. Cytotoxic CD4⁺ T cells may function similarly to kill infected target cells expressing MHC class II. Cytotoxic CD8⁺ T cells also have the potential to kill infected reticulocytes that transiently retain expression of MHC. B cells and CD4⁺ and CD8⁺ T cells are subject to regulation by other αβ T cells, including Tregs, IL-27-secreting CD4⁺ T cells, and Tr1 cells (the latter two subsets are not depicted). γδ T cells are activated in response to liver and blood-stage infection in response to unknown cues. These cells express cytokines that may include IFN-γ and myeloid activating factors like M-CSF. γδ T cells likely promote blood and liver stage parasite clearance by orchestrating and amplifying the activity of phagocytes. The contributions of Th17 and Th2 cells are less clear, but may be related to either recruiting and activating phagocytes or promoting Plasmodium-specific GC B cell reactions.