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

Louis Schofield, Lisa J. Ioannidis, Stephan Karl, Leanne J. Robinson, Qiao Y. Tan, Daniel P. Poole, Inoni Betuela, Danika L. Hill, Peter M. Siba, Diana S. Hansen, Ivo Mueller, Emily M. Eriksson

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: γδ 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. Methods: We 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. 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 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). 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 γδ T cell immunoregulation. Furthermore, we show that TIM3 represents an important γδ T cell regulatory component involved in minimizing malaria symptoms.

Original languageEnglish
Article number114
Number of pages15
JournalBMC Medicine
Volume15
Issue number1
DOIs
Publication statusPublished - 15 Jun 2017

Keywords

  • IL-12
  • IL-18
  • Malaria
  • Plasmodium
  • TIM3
  • γδ T cells

Cite this

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 ; Eriksson, Emily M. / 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. In: BMC Medicine. 2017 ; Vol. 15, No. 1.
@article{1983dede6ada484ca511a7acd9b291e2,
title = "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 = "Background: γδ 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. Methods: We 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. 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 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). 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 γδ T cell immunoregulation. Furthermore, we show that TIM3 represents an important γδ T cell regulatory component involved in minimizing malaria symptoms.",
keywords = "IL-12, IL-18, Malaria, Plasmodium, TIM3, γδ T cells",
author = "Louis Schofield and Ioannidis, {Lisa J.} and Stephan Karl and Robinson, {Leanne J.} and Tan, {Qiao Y.} and Poole, {Daniel P.} and Inoni Betuela and Hill, {Danika L.} and Siba, {Peter M.} and Hansen, {Diana S.} and Ivo Mueller and Eriksson, {Emily M.}",
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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. / 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; Eriksson, Emily M.

In: BMC Medicine, Vol. 15, No. 1, 114, 15.06.2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - 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

AU - Schofield, Louis

AU - Ioannidis, Lisa J.

AU - Karl, Stephan

AU - Robinson, Leanne J.

AU - Tan, Qiao Y.

AU - Poole, Daniel P.

AU - Betuela, Inoni

AU - Hill, Danika L.

AU - Siba, Peter M.

AU - Hansen, Diana S.

AU - Mueller, Ivo

AU - Eriksson, Emily M.

PY - 2017/6/15

Y1 - 2017/6/15

N2 - Background: γδ 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. Methods: We 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. 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 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). 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 γδ T cell immunoregulation. Furthermore, we show that TIM3 represents an important γδ T cell regulatory component involved in minimizing malaria symptoms.

AB - Background: γδ 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. Methods: We 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. 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 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). 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 γδ T cell immunoregulation. Furthermore, we show that TIM3 represents an important γδ T cell regulatory component involved in minimizing malaria symptoms.

KW - IL-12

KW - IL-18

KW - Malaria

KW - Plasmodium

KW - TIM3

KW - γδ T cells

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U2 - 10.1186/s12916-017-0883-8

DO - 10.1186/s12916-017-0883-8

M3 - Article

VL - 15

JO - BMC Medicine

JF - BMC Medicine

SN - 1741-7015

IS - 1

M1 - 114

ER -