Synergistic effect of IL-12 and IL-18 induces TIM3 regulation of γδ T cell function and decreases the risk of clinical malaria in children living in Papua New Guinea

Abstract

Backgroundγδ T cells are important for both protective immunity and immunopathogenesis during malaria infection. However, the immunological processes determining beneficial or detrimental effects on disease outcome remain elusive. The aim of this study was to examine expression and regulatory effect of the inhibitory receptor T-cell immunoglobulin domain and mucin domain 3 (TIM3) on γδ T cells. While TIM3 expression and function on conventional αβ T cells have been clearly defined, the equivalent characterization on γδ T cells and associations with disease outcomes is limited. This study investigated the functional capacity of TIM3+ γδ T cells and the underlying mechanisms contributing to TIM3 upregulation and established an association with malaria disease outcomes.MethodsWe analyzed TIM3 expression on γδ T cells in 132 children aged 5–10 years living in malaria endemic areas of Papua New Guinea. TIM3 upregulation and effector functions of TIM3+ γδ T cells were assessed following in vitro stimulation with parasite-infected erythrocytes, phosphoantigen and/or cytokines. Associations between the proportion of TIM3-expressing cells and the molecular force of infection were tested using negative binomial regression and in a Cox proportional hazards model for time to first clinical episode. Multivariable analyses to determine the association of TIM3 and IL-18 levels were conducted using general linear models. Malaria infection mouse models were utilized to experimentally investigate the relationship between repeated exposure and TIM3 upregulation.ResultsThis study demonstrates that even in the absence of an active malaria infection, children of malaria endemic areas have an atypical population of TIM3-expressing γδ T cells (mean frequency TIM3+ of total γδ T cells 15.2% ± 12). Crucial factors required for γδ T cell TIM3 upregulation include IL-12/IL-18, and plasma IL-18 was associated with TIM3 expression (P = 0.002). Additionally, we show a relationship between TIM3 expression and infection with distinct parasite clones during repeated exposure. TIM3+ γδ T cells were functionally impaired and were associated with asymptomatic malaria infection (hazard ratio 0.54, P = 0.032).ConclusionsCollectively our data demonstrate a novel role for IL-12/IL-18 in shaping the innate immune response and provide fundamental insight into aspects of γδ T cell immunoregulation. Furthermore, we show that TIM3 represents an important γδ T cell regulatory component involved in minimizing malaria symptoms.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0883-8) contains supplementary material, which is available to authorized users.

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

“…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. 49 Similarly, previously infected with P. vivax (between 2 and 9 months prior) but are no longer exposed, the frequencies of exhaustion markers on γδ T cells and total T lymphocytes were not significantly different from the frequencies in healthy controls, suggesting exhaustion is driven by continuous exposure to P. vivax and not maintained after parasite loads are eliminated by treatment.…”

“…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 . Similarly, our data demonstrate upregulated expression of the exhaustion markers‐Tim‐3, Lag‐3 and CTLA‐4 on γδ T cells in persistently exposed individuals living in the endemic region.…”

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.…”

Immune effector mechanisms in malaria: An update focusing on human immunity

“…There has been renewed interest in understanding immunoregulation of γδ T cells in the field of malaria (Figure and reviewed in ), as they are a major source of IFNγ and have been shown to inhibit blood‐stage infections . γδ T cells are unconventional in that their TCR recognize nonpeptide, phospho‐antigens and do not require MHC‐restriction for antigen presentation, as needed for αβ T cells; therefore, they respond rapidly to infection similar to NK cells.…”

“…There has been renewed interest in understanding immunoregulation of γδ T cells in the field of malaria ( Figure 5 and reviewed in 132 ), as they are a major source of IFNγ and have been shown to inhibit blood-stage infections. [133][134][135][136] γδ T cells are unconventional in that their TCR recognize nonpeptide, phospho-antigens and do not require MHC-restriction for antigen presentation, as needed for αβ T F I G U R E 5 Gamma-Delta T cell immunity during Plasmodium falciparum blood-stage infections. Early in a primary P. falciparum bloodstage infection, Vγ9 + Vδ2 + T cells (dark blue cells) produce the largest quantity of IFNγ.…”