IL-17A/IFN-γ producing γδ T cell functional dichotomy impacts cutaneous leishmaniasis in mice

γδ T cells play diverse roles in immune responses, producing either interleukin (IL)-17A or interferon γ (IFN-γ). Here, we investigated the impact of this functional dichotomy on cutaneous leishmaniasis. We demonstrate that in Sv129 mice susceptible to Leishmania amazonensis, Vγ4+ γδ T cells are the main source of IL-17A. In type 1 IFN receptor-deficient (A129) mice with heightened susceptibility, there is an increased frequency of IL-17A-producing γδ T cells. L. amazonensis' lipophosphoglycan induces these IL-17A-producing γδ T cells. Notably, C57BL/6 mice deficient in γδ T cells or IL-17 receptor exhibit smaller lesions, indicating a pathogenic role of IL-17A-producing γδ T cells in cutaneous leishmaniasis. Conversely, adoptive transfer of fluorescence-activated cell sorting (FACS)-sorted γδ T cells lead to an accumulation of IFN-γ-producing γδ T cells, associated with control of lesion development. On the other hand, adoptive transfer of FACS-sorted IFN-γ-deficient γδ T cells abolished the control of lesion development. These data demonstrate a pathophysiological dichotomy in which IL-17A-producing γδ T cells promote pathogenesis, while IFN-γ-producing γδ T cells offer therapeutic potential in cutaneous leishmaniasis.