Table 1.
γδ T cell responses to human malaria and associations with clinical outcomes.
| Author, year | Country | Cohort | γδ T cell subset | Impact of malaria exposure on γδ T cell activation and function | Associations between γδ T cell features and clinical outcomes |
|---|---|---|---|---|---|
| STUDIES OF MALARIA-NAÏVE TRAVELERS | |||||
| Roussilhon et al. (26) | France | Adults; acute Pf | All γδ | Expand after infection and remain elevated for months; subset respond in vitro to Pf schizont extract | |
| Howard et al. (27) | France | Adults; acute Pf | Vγ9Vδ2 | In vivo exposure and in vitro stimulation associated with increased surface expression of APC-associated markers, induce naive αβ T-cell responses, cross present soluble prototypical protein to antigen-specific CD8+ T cells | |
| STUDIES OF INDIVIDUALS IN MALARIA-ENDEMIC REGIONS | |||||
| Goodier et al. (28) | Benin | Adults and children | Vγ9+ and Vδ1+ | Majority of γδ T cells are Vδ1+; Vγ9+ cells not elevated compared to malaria-naïve controls but do proliferate after in vitro Pf stimulation | |
| Ho et al. (29) | Thailand | Age not reported; acute Pf | All γδ | Expand after acute infection and remain elevated for several weeks | |
| Hviid et al. (30) | Ghana | Children; acute Pf | Vδ1+ | Increase after treatment and produce pro-inflammatory cytokines | |
| D'Ombrain et al. (31) | Papua New Guinea | Children | All γδ | Produce IFNγ following in vitro Pf stimulation | IFNγ from γδ and αβ T cells associated with immunity to symptomatic infection |
| Cairo et al. (32) | Cameroon | Neonates | Vδ2+ | Placental malaria associated with increased proportions of central memory Vγ2Vδ2 cells in cord blood and altered Vγ2 chain repertoire ex vivo or after stimulation | |
| Stanisic et al. (33) | Papua New Guinea | Children | All γδ | Produce TNF, MIP-1β, and MIP-1α following in vitro Pf stimulation | Increased TNF from γδ T cells and monocytes associated with severe malaria |
| Jagannathan et al. (34) | Uganda | Children | Vδ2+ | Repeated infection associated with loss and dysfunction of Vδ2+ cells and increased Vδ2 expression of immunoregulatory genes including Tim3, CD57, CD16 | Loss and dysfunction of Vδ2+ cells associated with clinical tolerance to infection |
| Farrington et al. (35) | Uganda | Children | Vδ2+ | Frequencies and function lower and CD16 upregulated among children with high prior malaria exposure; antimalarial chemoprevention associated with enhanced Vδ2+ cytokine production | |
| Hsu et al. (36) | Malawi | Neonates | Vδ2+ | Upregulate PD1 shortly after activation; after engagement of PD1 with PDL1, show dampened TNFα production and degranulation | |
| Schofield et al. (37) | Papua New Guinea | Children | All γδ | Elevated Tim-3+ γδ T cells across whole cohort; IL-12 and IL-18 contribute to upregulation | Higher proportions of Tim-3+ γδ T cells associated with asymptomatic malaria infection |
| Taniguchi et al. (38) | Laos | Adults and children; uncomplicated malaria | Non-Vδ2 | Expand and produce IL-10 and IFNγ | |
| Jagannathan et al. (39) | Uganda | Children | Vδ2+ | In vivo proliferative response attenuated with repeated exposure; repeated infection associated with loss and dysfunction of Vδ2+ cells | Higher pro-inflammatory cytokine production associate with protection from subsequent infection as well as increased odds of symptoms once infected |
| VACCINATION STUDIES | |||||
| Teirlinck et al. (40); Roestenberg et al. (41) | The Netherlands | Malaria naïve adults; controlled-human malaria infection (CHMI) + chemoprophylaxis | All γδ | Produce IFNγ, even a year after infection | Long-term functional responses associated with protection against re-infection |
| Seder et al. (42); Ishizuka et al. (43) | USA | Malaria naïve adults; attenuated PfSPZ vaccination | Vδ2+ | Expand after vaccination | Higher frequencies correlate with protection after CHMI |
| Mordmüller et al. (44) | Germany | Malaria naïve adults; non-irradiated PfSPZ vaccination + chemoprophylaxis | Vγ9Vδ2 | Expand in dose-dependent manner and produce IFNγ | |
| Lyke et al. (45) | USA | Malaria naïve adults; attenuated PfSPZ vaccination | Vδ2+ | Cell frequency increase after each vaccination and show activated phenotype | |
| Zaidi et al. (46) | Mali | Malaria-exposed adults; irradiated PfSPZ vaccination | Vδ2+ | Vδ2+ T cells significantly elevated among vaccinees who remain uninfected during transmission season | |