The Impact of Malaria Parasites on Dendritic Cell-T Cell Interaction

Abstract

Malaria is caused by apicomplexan parasites of the genus Plasmodium. While infection continues to pose a risk for the majority of the global population, the burden of disease mainly resides in Sub-Saharan Africa. Although immunity develops against disease, this requires years of persistent exposure and is not associated with protection against infection. Repeat infections occur due to the parasite's ability to disrupt or evade the host immune responses. However, despite many years of study, the mechanisms of this disruption remain unclear. Previous studies have demonstrated a parasite-induced failure in dendritic cell (DCs) function affecting the generation of helper T cell responses. These T cells fail to help B cell responses, reducing the production of antibodies that are necessary to control malaria infection. This review focuses on our current understanding of the effect of Plasmodium parasite on DC function, DC-T cell interaction, and T cell activation. A better understanding of how parasites disrupt DC-T cell interactions will lead to new targets and approaches to reinstate adaptive immune responses and enhance parasite immunity.

Keywords: DC-T cell interaction; T cells; T helper cells; Tfh; dendritic cells; malaria.

Figure 1

The asexual life cycle of Plasmodium parasite begins when an infected mosquito injects highly motile sporozoites into the skin of the host. The sporozorites enters the bloodstream and migrates to the liver, where it traverses multiple hepatocytes before infecting one. Inside the hepatocyte the sporozoite undergoes pre-erythrocytic schizogony forming merozoites that accumulate and bud off the hepatocyte in structures called merosomes. Merosomes enter the bloodstream and release merozoites which invade RBC, initiating the erythrocytic stage of asexual development. At this stage the parasite develops inside the RBC in distinct forms namely the ring, trophozoite, and schizont form. The schizont, lyses releasing merozoites into the blood stream which reinvade RBCs starting a fresh round of asexual development. After rounds of erythrocytic schizogony some of the asexual parasites develop into gametocytes and are taken up by a mosquito during a blood meal. Dendritic cells can interact with sporozoites in the dermis (A), the liver (B) and the blood and spleen (C). The DCs at each site encounter the parasite in its different forms (Figure was created using BioRender).

Figure 2

T cell activation or deactivation requires three signals from DCs. (A) T cell activation requires signal 1 in the form of TCR interacting with antigen-MHC complex which is key in innating downward signaling through ITAMs. Interaction of co-stimulatory molecules (interaction of CD40-CD40L, and CD80/86-CD28) form part of signal 2 as they work in tandem with TCR-antigen-MHC complex to enhance TCR signaling and initiate T cell proliferation. Signal 3 comes from DCs in the form of cytokines, and in CD4 T cells it is key in dictating which subset it will differentiate into. (B) Co-inhibitory molecules also form part of the second signal but unlike co-stimulatory molecules they inhibit TCR signaling, thus dampening immune responses. Interaction of PD-1 with PD-L1 inhibits T cell activation, while CTLA4 competes for binding with CD28 to CD80/86 and successful binding of CTLA4 to CD80/86 nullifies CD28-CD80/86 activation signal. Malaria has been shown to induce expression of PD-1, LAG3 and CTLA-4 on CD4 T cells, and this inhibits the activation signal from DCs (Figure was created using BioRender).

Figure 3

Tfh development and function. (A) Tfh differentiation begins when an activated DC primes a naïve CD4 T cells. Interaction between ICOS on CD4 and ICOS-L on DCs results in upregulation of Bcl-6 and CXCR5 on CD4 T cells. IL-12 and IL-6, help maintain expression of Bcl-6, and IL-12 induces upregulation of IL-21 which is essential for survival of the pre-Tfh cell. Initial CD4 T cell activation also results in upregulation of PD-1. The Bcl-6+CXCR5+ PD-1+ pre–Tfh cell then migrates to the T cell–B cell border. At the same time, antigen-activated B cells upregulate CCR7 and migrates from the B cell follicle to the T cell–B cell border. (B) At the T cell–B cell border, the pre-Tfh cell engages with the B cell. Interaction between antigen-MHC on B cells with TCR on pre-Tfh, and ICOSL (B cell) with ICOS (pre-Tfh cell), fully commits the cell to Tfh lineage. This results in upregulation and maintenance of Bcl-6, SAP, and CXCR5, while downregulating CCR7 on T cells. (C) The Tfh and B cells move deeper into the B cell follicle forming GCs. Tfh cells in the GCs promotes B-cell maturation, class switching and affinity maturation via the cytokines, IL-21 and IL-4, and the molecules, CD40L and PD-1. Both Tfh and GC B-cell are necessary for generation of B-cell memory and long-lived plasma cells. (D,E) Plasmodium-induces polarization of T follicular helper (Tfh) cells to Th1 like phenotytpe that expresses Tbet PD-1, CXCR5, CXCR3 and contributes to the inefficient acquisition of humoral immunity to malaria. Malaria infection in mice and humans induces secretion of Th1-polarizing cytokine that drive the activation of Th1-like Tfh cells that exhibit impaired B cell helper function, thus contributing to germinal center dysfunction and suboptimal antibody responses (Figure was created using BioRender).