GITR Activation Positively Regulates Immune Responses against Toxoplasma gondii

PLoS One. 2016 Mar 30;11(3):e0152622. doi: 10.1371/journal.pone.0152622. eCollection 2016.

Abstract

Toxoplasma gondii is a widespread parasite responsible for causing clinical diseases especially in pregnant and immunosuppressed individuals. Glucocorticoid-induced TNF receptor (GITR), which is also known as TNFRS18 and belongs to the TNF receptor superfamily, is found to be expressed in various cell types of the immune system and provides an important costimulatory signal for T cells and myeloid cells. However, the precise role of this receptor in the context of T. gondii infection remains elusive. Therefore, the current study investigated the role of GITR activation in the immunoregulation mechanisms induced during the experimental infection of mice with T. gondii. Our data show that T. gondii infection slightly upregulates GITR expression in Treg cells and B cells, but the most robust increment in expression was observed in macrophages and dendritic cells. Interestingly, mice infected and treated with an agonistic antibody anti-GITR (DTA-1) presented a robust increase in pro-inflammatory cytokine production at preferential sites of parasite replication, which was associated with the decrease in latent brain parasitism of mice under treatment with DTA-1. Several in vivo and in vitro analysis were performed to identify the cellular mechanisms involved in GITR activation upon infection, however no clear alterations were detected in the phenotype/function of macrophages, Tregs and B cells under treatment with DTA-1. Therefore, GITR appears as a potential target for intervention during infection by the parasite Toxoplasma gondii, even though further studies are still necessary to better characterize the immune response triggered by GITR activation during T. gondii infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / pharmacology
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / parasitology
  • Female
  • Glucocorticoid-Induced TNFR-Related Protein / antagonists & inhibitors
  • Glucocorticoid-Induced TNFR-Related Protein / immunology*
  • Male
  • Mice
  • Myeloid Cells / immunology*
  • Myeloid Cells / parasitology
  • Pregnancy
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / parasitology
  • Toxoplasma / immunology*
  • Toxoplasmosis / drug therapy
  • Toxoplasmosis / immunology*

Substances

  • Antibodies, Neutralizing
  • Glucocorticoid-Induced TNFR-Related Protein
  • Tnfrsf18 protein, mouse

Grants and funding

This work was supported by the following Brazilian research funding agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, 309011/2013-2), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, AUX-PE-Parasitologia-1348/2011) and Fundação de Amparo a Pesquisa de Minas Gerais (FAPEMIG, RED-00013-14, CVZ-PPM-00784-15, APQ01313-14). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.