Opsonized antigen activates Vδ2+ T cells via CD16/FCγRIIIa in individuals with chronic malaria exposure

Vγ9Vδ2 T cells rapidly respond to phosphoantigens produced by Plasmodium falciparum in an innate-like manner, without prior antigen exposure or processing. Vδ2 T cells have been shown to inhibit parasite replication in vitro and are associated with protection from P. falciparum parasitemia in vivo. Although a marked expansion of Vδ2 T cells is seen after acute malaria infection in naïve individuals, repeated malaria causes Vδ2 T cells to decline both in frequency and in malaria-responsiveness, and to exhibit numerous transcriptional and phenotypic changes, including upregulation of the Fc receptor CD16. Here we investigate the functional role of CD16 on Vδ2 T cells in the immune response to malaria. We show that CD16+ Vδ2 T cells possess more cytolytic potential than their CD16- counterparts, and bear many of the hallmarks of mature NK cells, including KIR expression. Furthermore, we demonstrate that Vδ2 T cells from heavily malaria-exposed individuals are able to respond to opsonized P.falciparum-infected red blood cells through CD16, representing a second, distinct pathway by which Vδ2 T cells may contribute to anti-parasite effector functions. This response was independent of TCR engagement, as demonstrated by blockade of the phosphoantigen presenting molecule Butyrophilin 3A1. Together these results indicate that Vδ2 T cells in heavily malaria-exposed individuals retain the capacity for antimalarial effector function, and demonstrate their activation by opsonized parasite antigen. This represents a new role both for Vδ2 T cells and for opsonizing antibodies in parasite clearance, emphasizing cooperation between the cellular and humoral arms of the immune system.
Author summary T cells that express the Vδ2 and Vγ9 TCR chains (Vδ2 T cells) have been shown to play an important role in controlling parasitemia during P.falciparum infection. A better understanding of how these cells interact with malaria parasites to control infection is necessary. We have previously shown that after multiple P. falciparum infections, Vδ2 T cells decrease in frequency, become less responsive to TCR stimulation, and upregulate the Fc receptor CD16. Here we investigate whether Vδ2 T cells from chronically malaria-exposed individuals can be activated directly through CD16 to release proinflammatory cytokines and degranulate. We show that in these individuals, TCR is downregulated on CD16+ Vδ2 T cells, and that these cells are more likely to express a variety of cytotoxic effector molecules. Importantly, we show that these CD16+ Vδ2 T cells can be activated directly through CD16, independent of TCR, by antibody bound to parasite antigen. These results are notable because they indicate many Vδ2 T cells from chronically-exposed individuals may not be exhausted but instead favor an alternative activation pathway, one that cooperates with a mature anti-malarial antibody response.