Novel M-CSF-producing γδ T cells protect against recurrent malaria

Abstract

In 2016, there were 216 million malaria cases – 445,000 of which resulted in deaths. Despite overwhelming evidence that γδ T cells strongly respond during malaria infection and vaccination, their functional and phenotypic characteristics remain the least understood facets of the adaptive immune response. Therefore, we studied the role of these cells in human and mouse malaria. In both Plasmodium falciparum-infected subjects and in P. chabaudi-infected mice, we found γδ T cells expanding rapidly after resolution of acute parasitemia, in contrast to αβ T cells that expanded at the acute stage and then declined. Silencing the murine γδ T cells led to recurrent rounds of Plasmodium parasitemia. Single-cell T cell receptor sequencing of the expanded mouse cells revealed oligoclonal γδ T cells restricted to the TRAV15N-1 (Vδ6.3) V-region and converging complementarity-determining region 3 (CDR3) motifs. Also, RNA-seq of the expanded γδ T cells showed an unexpected transcriptional profile characterized by myeloid-modulating factors, previously unseen in γδ T cells. The expanded TRAV15N-1 γδ T cells abundantly produced M-CSF, which was necessary for preventing parasitemic recurrence. Interestingly, αβ T cells were the major source of M-CSF during acute infection, while γδ T cells filled that role during the post-acute stage. We have uncovered a novel γδ T cell subset that fills a protective role in the late stage of malaria. These cells could provide the mechanism for other observed correlations between γδ T cell and myeloid activity in cancer and infectious disease.