γδ T cells suppress Plasmodium falciparum blood-stage infection by direct killing and phagocytosis

Abstract

Activated Vγδ9Vδ2 (γδ2) T lymphocytes that sense parasite-produced phosphoantigens are expanded in Plasmodium falciparum -infected patients. Although previous studies suggested that γδ2 T cells help control erythrocytic malaria, whether γδ2 T cells recognize infected red blood cells (iRBCs) was uncertain. Here we show that iRBCs stained for the phosphoantigen sensor, butyrophilin 3A1 (BTN3A1). γδ2 T cells formed immune synapses and lysed iRBCs in a contact, phosphoantigen, BTN3A1 and degranulation-dependent manner, killing intracellular parasites. Granulysin released into the synapse lysed iRBCs and delivered death-inducing granzymes to the parasite. All intra-erythrocytic parasites were susceptible, but schizonts were most sensitive. A second protective γδ2 T cell mechanism was identified. In the presence of patient serum, γδ2 T cells phagocytosed and degraded opsonized iRBCs in a CD16-dependent manner, decreasing parasite multiplication. Thus, γδ2 T cells have two ways to control blood stage malaria – γδT cell antigen receptor (TCR)-mediated degranulation and phagocytosis of antibody-coated iRBCs.

Systems analysis shows a role of cytophilic antibodies in shaping innate tolerance to malaria

“…In agreement with previous reports, we observed expanding γδ T cells after the initial inflammatory response in response to the infection (45,46). gd T cells are suggested to have an important role in the control of malaria (29) and direct anti-parasite functions during the blood stage have been reported (24). In this study, we observed that the acute phase inflammatory response was positively associated with expansion of Vd2 + gd T cells, and further that this was strongly impacted by previous malaria exposure, resulting in a dampened inflammatory response and less gd T cell expansion.…”

“…Vd2 + gd T cells are known to activate and expand during a primary P. falciparum infection in response to malaria phosphoantigens and that their activity is modulated upon subsequent infections (47). Given the recently described role of Vd2 + gd T cells in antiparasitic activities via antibody-CD16 dependent phagocytosis of infected erythrocytes and cytotoxicity (24,25), associations to possible activity modulating factors are of interest. The benefit of reduced expansion of gd T cells due to a dampened inflammatory response could be to reduce overall inflammatory responses, which are otherwise potentially detrimental to the host (48).…”

“…Here, we could show that primary infected individuals have significantly higher levels of proinflammatory cytokines at the acute phase, as well as a significantly larger expansion of Vδ2 + γδ T cells after the acute phase compared with individuals previously exposed to malaria. The Vδ2 + subset of γδ T cells have been shown to play an important role in combating blood stage malaria, via TCR-induced cytotoxicity and CD16 mediated phagocytosis (24,25). We therefore focused on characterizing the CD16 + Vδ2 + γδ T cell response further using linear-mixed effects models to assess the impact of previous exposure to parasites on gd T cell functional markers.…”

A Profound Membrane Reorganization Defines Susceptibility of Plasmodium falciparum Infected Red Blood Cells to Lysis by Granulysin and Perforin

“…Therefore, to prevent malaria-associated morbidity and mortality tight control of parasitemia is essential. We previously demonstrated, and it was very recently independently confirmed (54), that the lymphocyte subset bearing the gd T cell receptor contributes critically to the inhibition of parasite growth in the blood phase. The inhibition of late stage parasite depended on the expression of GNLY and GzmB but was independent of PFN.…”

Targeting butyrophilins for cancer immunotherapy

“…The important role γδ T cells play (including Vγ9Vδ2 + T cells) in immune responses to infections in humans has been well established [5][6][7][8][9][10]. Because of their characterized cytotoxic potential against a variety of tumor cells in vitro [11,12] and in vivo in mouse models [13][14][15], they are widely investigated for their putative roles in cancer immunity and therapy (Box 1).…”