A Macrophage Colony-Stimulating-Factor-Producing γδ T Cell Subset Prevents Malarial Parasitemic Recurrence

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SummaryDespite evidence that γδ T cells play an important role during malaria, their precise role remains unclear. During murine malaria induced by Plasmodium chabaudi infection and in human P. falciparum infection, we found that γδ T cells expanded rapidly after resolution of acute parasitemia, in contrast to αβ T cells that expanded at the acute stage and then declined. Single-cell sequencing showed that TRAV15N-1 (Vδ6.3) γδ T cells were clonally expanded in mice and had convergent complementarity-determining region 3 sequences. These γδ T cells expressed specific cytokines, M-CSF, CCL5, CCL3, which are known to act on myeloid cells, indicating that this γδ T cell subset might have distinct functions. Both γδ T cells and M-CSF were necessary for preventing parasitemic recurrence. These findings point to an M-CSF-producing γδ T cell subset that fulfills a specialized protective role in the later stage of malaria infection when αβ T cells have declined.Graphical AbstractHighlightsγδ T cells are expanded and activated in the later stages of mouse and human malariaMurine γδ T cells prevent late stage Plasmodium chabaudi recurrenceTRAVN-1+ (Vδ6.3+) γδ T cells clonally expand in the blood, spleen, lung, and liverExpanded γδ T cells express M-CSF, which protects against parasitemic recurrenceγδ T cell frequency increases late during mouse and human malaria. Mamedov et al. show that oligoclonal TRAV15N-1 (Vδ6.3) γδ T cells expand across various tissues and prevent late-stage parasitemic recurrence. These protective γδ T cells exhibit a distinct transcriptional profile that includes abundantly expressed M-CSF, which protects against Plasmodium recurrence.

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