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

Abstract

{gamma}{delta} T cells are innate-like lymphocytes with pleiotropic roles in immune responses to pathogens, often ascribed to their IL-17A-producing or IFN-{gamma}-producing {gamma}{delta} T cell subsets. Here we investigated the impact of this functional dichotomy on cutaneous leishmaniasis, a set of neglected diseases caused by parasites of the Leishmania genus. We demonstrate that in Sv129 mice susceptible to Leishmania amazonensis, V{gamma}4+ {gamma}{delta} T cells are the main source of IL-17A. Furthermore, in type 1 interferon receptor-deficient (A129) mice presenting increased susceptibility to infection, there is a higher frequency of IL-17A-producing {gamma}{delta} T cells when compared to wild-type mice. Mechanistically, we demonstrate that lipophosphoglycan (LPG) of L. amazonensis induces IL-17A-producing {gamma}{delta} T cells. Importantly, C57Bl/6 mice deficient in {gamma}{delta} T cells or in IL-17 receptor (IL-17RA) show reduced lesion sizes, consistent with a pathogenic role of IL-17A-producing {gamma}{delta} T cells in cutaneous leishmaniasis. Conversely, the adoptive transfer of FACS-sorted {gamma}{delta} T cells led to an accumulation of IFN-{gamma}-producing {gamma}{delta} T cells in various susceptible strains of mice which associated with control of lesion development. These data demonstrate a pathophysiological dichotomy in which IL-17A-producing {gamma}{delta} T cells promote pathogenesis, whereas IFN-{gamma}-producing {gamma}{delta} T cells display therapeutic potential in cutaneous leishmaniasis.