Schofield, Louis, Ioannidis, Lisa J., Karl, Stephan, Robinson, Leanne J., Tan, Qiao Y., Poole, Daniel P., Betuela, Inoni, Hill, Danika L., Siba, Peter M., Hansen, Diana S., Mueller, Ivo, and Eriksson, Emily M/ (2017) Synergistic effect of IL-12 and IL-18 induces TIM3 regulation of gamma delta T cell function and decreases the risk of clinical malaria in children living in Papua New Guinea. BMC Medicine, 15. 114.

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Abstract

Background: gamma delta 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 gamma delta T cells. While TIM3 expression and function on conventional aa T cells have been clearly defined, the equivalent characterization on gamma delta T cells and associations with disease outcomes is limited. This study investigated the functional capacity of TIM3+gamma delta T cells and the underlying mechanisms contributing to TIM3 upregulation and established an association with malaria disease outcomes.

Methods: We analyzed TIM3 expression on gamma delta 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+gamma delta 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.

Results: This study demonstrates that even in the absence of an active malaria infection, children of malaria endemic areas have an atypical population of TIM3-expressing gamma delta cells (mean frequency TIM3+ of total gamma delta T cells 15.2% +/- 12). Crucial factors required for gamma delta 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+gamma delta T cells were functionally impaired and were associated with asymptomatic malaria infection (hazard ratio 0.54, P = 0.032).

Conclusions: Collectively our data demonstrate a novel role for IL-12/IL-18 in shaping the innate immune response and provide fundamental insight into aspects of gamma delta T cell immunoregulation. Furthermore, we show that TIM3 represents an important.d T cell regulatory component involved in minimizing malaria symptoms.

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