title: Loss and dysfunction of Vδ2⁺ γδ T cells are associated with clinical tolerance to malaria.
abstract: Although clinical immunity to malaria eventually develops among children living in endemic settings, the underlying immunologic mechanisms are not known. The Vδ2(+) subset of γδ 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 naïve hosts, but their role in mediating immunity in children repeatedly exposed to malaria is unclear. We evaluated γδ 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 Vδ2(+) γδ 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 Vδ2(+) γδ 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 Vδ2(+) γδ T cells that may facilitate immunological tolerance of the parasite.
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Jagannathan
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Charlie C
authors.initials: CC
authors.lastname: Kim
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Greenhouse
authors.affiliation: Infectious Diseases Research Collaboration, P.O. Box 7475, Kampala, Uganda.
authors.forename: Felistas
authors.initials: F
authors.lastname: Nankya
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Bowen
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Ijeoma
authors.initials: I
authors.lastname: Eccles-James
authors.affiliation: Infectious Diseases Research Collaboration, P.O. Box 7475, Kampala, Uganda.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Muhindo
authors.affiliation: Infectious Diseases Research Collaboration, P.O. Box 7475, Kampala, Uganda.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Arinaitwe
authors.affiliation: Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Jordan W
authors.initials: JW
authors.lastname: Tappero
authors.affiliation: Department of Medicine, Makerere University College of Health Sciences, P.O. Box 7051, Kampala, Uganda.
authors.forename: Moses R
authors.initials: MR
authors.lastname: Kamya
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, CA 94110, USA. Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94110, USA. margaret.feeney@ucsf.edu.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Feeney
mesh_terms: D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D020869:Gene Expression Profiling; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007109:Immunity; D056747:Immunomodulation; D015994:Incidence; D007223:Infant; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000235:genetics / Q000276:immunology*; D018512:Parasitemia / Q000276:immunology; D010963:Plasmodium falciparum / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D016896:Treatment Outcome; D014454:Uganda / Q000453:epidemiology
chemical_list: D016692:Receptors, Antigen, T-Cell, gamma-delta