Loss and dysfunction of Vδ2+ γδ T cells are associated with clinical tolerance to malaria

Although clinical immunity to malaria eventually develops among children living in endemic settings, the underlying immunologic mechanisms are not known. The V delta 2(+) subset of gamma delta T cells have intrinsic reactivity to malaria antigens, can mediate killing of Plasmodium falciparum merozoites, and expand markedly in vivo after malaria infection in previously nave hosts, but their role in mediating immunity in children repeatedly exposed to malaria is unclear. We evaluated gamma delta T cell responses to malaria among 4-year-old children enrolled in a longitudinal study in Uganda. We found that repeated malaria was associated with reduced percentages of V delta 2(+) gamma delta T cells in peripheral blood, decreased proliferation and cytokine production in response to malaria antigens, and increased expression of immunoregulatory genes. Further, loss and dysfunction of proinflammatory V delta 2(+) gamma delta T cells were associated with a reduced likelihood of symptoms upon subsequent P. falciparum infection. Together, these results suggest that repeated malaria infection during childhood results in progressive loss and dysfunction of V delta 2(+) gamma delta T cells that may facilitate immunological tolerance of the parasite.