Vδ2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure

Abstract

Vδ2+ γδ T cells are semi-innate T cells that expand markedly following P. falciparum (Pf) infection in naïve adults, but are lost and become dysfunctional among children repeatedly exposed to malaria. The role of these cells in mediating clinical immunity (i.e. protection against symptoms) to malaria remains unclear. We measured Vδ2+ T cell absolute counts at acute and convalescent malaria timepoints (n = 43), and Vδ2+ counts, cellular phenotype, and cytokine production following in vitro stimulation at asymptomatic visits (n = 377), among children aged 6 months to 10 years living in Uganda. Increasing age was associated with diminished in vivo expansion following malaria, and lower Vδ2 absolute counts overall, among children living in a high transmission setting. Microscopic parasitemia and expression of the immunoregulatory markers Tim-3 and CD57 were associated with diminished Vδ2+ T cell pro-inflammatory cytokine production. Higher Vδ2 pro-inflammatory cytokine production was associated with protection from subsequent Pf infection, but also with an increased odds of symptoms once infected. Vδ2+ T cells may play a role in preventing malaria infection in children living in endemic settings; progressive loss and dysfunction of these cells may represent a disease tolerance mechanism that contributes to the development of clinical immunity to malaria.

Exposure to Plasmodium vivax is associated with the increased expression of exhaustion markers on γδ T lymphocytes

“…Continuous exposure to P. falciparum is also associated with an increased level of Tim‐3 expression on γδ T cells in children, without any alteration in the expression of PD‐1 and Lag‐3, suggesting the use of distinct immunomodulatory pathways by γδ T cells to blunt inflammatory responses . Furthermore, children who were highly exposed to P. falciparum had significantly higher levels of Tim‐3 and CD57 on Vδ2 + T cells and reduced Vδ2 + T‐cell proinflammatory cytokine production . However, the expression of exhaustion markers on T lymphocytes during persistent exposure to P. vivax has remained poorly understood.…”

“…29 Furthermore, children who were highly exposed to P. falciparum had significantly higher levels of Tim-3 and CD57 on Vδ2 + T cells and reduced Vδ2 + T-cell proinflammatory cytokine production. 48 However, the expression of exhaustion markers on T lymphocytes during persistent exposure to P. vivax has remained poorly understood. Recently, a higher proportion of Tim-3+ γδ T cells were found in children continuously exposed to P. vivax, and these cells were unresponsive to in vitro stimulation.…”

Emerging role of γδ T cells in vaccine‐mediated protection from infectious diseases

“…[45][46][47][48] Frequencies of cd T-cell subsets, including Vd2 + , Vd2 À , activated CD11c + or CD16 + /Tim-3 + cd T cells, have all been associated with malaria exposure. [49][50][51][52][53][54][55][56] Higher frequencies and malaria-responsive cytokine production of Vd2 + T cells correlate with protection against subsequent infection in children living in endemic settings, 57,58 and in vitro, these cells perform cytotoxic, anti-parasitic functions. 59,60 Furthermore, these cells can also act as antigenpresenting cells, [61][62][63][64] which may further enhance the response to infection and/or vaccination.…”

Harnessing γδ T Cells as Natural Immune Modulators

“…However, upon subsequent infection, the numbers of γδ T cells drop, similar to the situation with long-term HIV infection. Nonetheless, higher numbers of functional Vδ2 T cells are correlated with greater protection from reinfection with Plasmodium and also increased symptoms upon infection, as they are sources of IFNγ and TNF-α [105]. Similarly, the first instance of bovine IL-17-producing cells was demonstrated and protects against a related parasite [106].…”