Abstract
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.
Highlights
Introduction γδT cells are believed to play an important role in the immune response to malaria
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
We investigate whether Vδ2 T cells from chronically malaria-exposed individuals can be activated directly through CD16 to release proinflammatory cytokines and degranulate
Summary
T cells are believed to play an important role in the immune response to malaria. These unconventional lymphocytes comprise up to 5% of peripheral blood T cells and exhibit features of both adaptive and innate immune cells. Γδ T cells expressing the Vδ2 and Vγ9 TCR chains are intrinsically reactive to malaria due to their activation by low-molecular weight phosphoantigens produced by the plasmodium apicoplast. Because BTN3a1 is ubiquitously expressed, this interaction is MHC-unrestricted and does not require professional antigen presenting cells. Vδ2 T cells act as innate-like effectors that can be rapidly activated during primary infection before an adaptive response has developed. The frequency and malariaresponsiveness of Vδ2 T cells has been shown to correlate with protection from parasitemia in naturally exposed Ugandan children and in malaria-naive volunteers immunized with attenuated Plasmodium falciparum sporozoites [14,15,16]
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