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Acute Malaria Induces PD1(+)CTLA4(+) Effector T Cells with Cell-Extrinsic Suppressor Function

In acute Plasmodium falciparum (P. falciparum) malaria, the pro- and anti-inflammatory immune pathways must be delicately balanced so that the parasitemia is controlled without inducing immunopathology. An important mechanism to fine-tune T cell responses in the periphery is the induction of coinhib...

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Autores principales: Mackroth, Maria Sophia, Abel, Annemieke, Steeg, Christiane, Schulze zur Wiesch, Julian, Jacobs, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089727/
https://www.ncbi.nlm.nih.gov/pubmed/27802341
http://dx.doi.org/10.1371/journal.ppat.1005909
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author Mackroth, Maria Sophia
Abel, Annemieke
Steeg, Christiane
Schulze zur Wiesch, Julian
Jacobs, Thomas
author_facet Mackroth, Maria Sophia
Abel, Annemieke
Steeg, Christiane
Schulze zur Wiesch, Julian
Jacobs, Thomas
author_sort Mackroth, Maria Sophia
collection PubMed
description In acute Plasmodium falciparum (P. falciparum) malaria, the pro- and anti-inflammatory immune pathways must be delicately balanced so that the parasitemia is controlled without inducing immunopathology. An important mechanism to fine-tune T cell responses in the periphery is the induction of coinhibitory receptors such as CTLA4 and PD1. However, their role in acute infections such as P. falciparum malaria remains poorly understood. To test whether coinhibitory receptors modulate CD4(+) T cell functions in malaria, blood samples were obtained from patients with acute P. falciparum malaria treated in Germany. Flow cytometric analysis showed a more frequent expression of CTLA4 and PD1 on CD4(+) T cells of malaria patients than of healthy control subjects. In vitro stimulation with P. falciparum-infected red blood cells revealed a distinct population of PD1(+)CTLA4(+)CD4(+) T cells that simultaneously produced IFNγ and IL10. This antigen-specific cytokine production was enhanced by blocking PD1/PDL1 and CTLA4. PD1(+)CTLA4(+)CD4(+) T cells were further isolated based on surface expression of PD1 and their inhibitory function investigated in-vitro. Isolated PD1(+)CTLA4(+)CD4(+) T cells suppressed the proliferation of the total CD4(+) population in response to anti-CD3/28 and plasmodial antigens in a cell-extrinsic manner. The response to other specific antigens was not suppressed. Thus, acute P. falciparum malaria induces P. falciparum-specific PD1(+)CTLA4(+)CD4(+) T(effector) cells that coproduce IFNγ and IL10, and inhibit other CD4(+) T cells. Transient induction of regulatory T(effector) cells may be an important mechanism that controls T cell responses and might prevent severe inflammation in patients with malaria and potentially other acute infections.
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spelling pubmed-50897272016-11-15 Acute Malaria Induces PD1(+)CTLA4(+) Effector T Cells with Cell-Extrinsic Suppressor Function Mackroth, Maria Sophia Abel, Annemieke Steeg, Christiane Schulze zur Wiesch, Julian Jacobs, Thomas PLoS Pathog Research Article In acute Plasmodium falciparum (P. falciparum) malaria, the pro- and anti-inflammatory immune pathways must be delicately balanced so that the parasitemia is controlled without inducing immunopathology. An important mechanism to fine-tune T cell responses in the periphery is the induction of coinhibitory receptors such as CTLA4 and PD1. However, their role in acute infections such as P. falciparum malaria remains poorly understood. To test whether coinhibitory receptors modulate CD4(+) T cell functions in malaria, blood samples were obtained from patients with acute P. falciparum malaria treated in Germany. Flow cytometric analysis showed a more frequent expression of CTLA4 and PD1 on CD4(+) T cells of malaria patients than of healthy control subjects. In vitro stimulation with P. falciparum-infected red blood cells revealed a distinct population of PD1(+)CTLA4(+)CD4(+) T cells that simultaneously produced IFNγ and IL10. This antigen-specific cytokine production was enhanced by blocking PD1/PDL1 and CTLA4. PD1(+)CTLA4(+)CD4(+) T cells were further isolated based on surface expression of PD1 and their inhibitory function investigated in-vitro. Isolated PD1(+)CTLA4(+)CD4(+) T cells suppressed the proliferation of the total CD4(+) population in response to anti-CD3/28 and plasmodial antigens in a cell-extrinsic manner. The response to other specific antigens was not suppressed. Thus, acute P. falciparum malaria induces P. falciparum-specific PD1(+)CTLA4(+)CD4(+) T(effector) cells that coproduce IFNγ and IL10, and inhibit other CD4(+) T cells. Transient induction of regulatory T(effector) cells may be an important mechanism that controls T cell responses and might prevent severe inflammation in patients with malaria and potentially other acute infections. Public Library of Science 2016-11-01 /pmc/articles/PMC5089727/ /pubmed/27802341 http://dx.doi.org/10.1371/journal.ppat.1005909 Text en © 2016 Mackroth et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Mackroth, Maria Sophia
Abel, Annemieke
Steeg, Christiane
Schulze zur Wiesch, Julian
Jacobs, Thomas
Acute Malaria Induces PD1(+)CTLA4(+) Effector T Cells with Cell-Extrinsic Suppressor Function
title Acute Malaria Induces PD1(+)CTLA4(+) Effector T Cells with Cell-Extrinsic Suppressor Function
title_full Acute Malaria Induces PD1(+)CTLA4(+) Effector T Cells with Cell-Extrinsic Suppressor Function
title_fullStr Acute Malaria Induces PD1(+)CTLA4(+) Effector T Cells with Cell-Extrinsic Suppressor Function
title_full_unstemmed Acute Malaria Induces PD1(+)CTLA4(+) Effector T Cells with Cell-Extrinsic Suppressor Function
title_short Acute Malaria Induces PD1(+)CTLA4(+) Effector T Cells with Cell-Extrinsic Suppressor Function
title_sort acute malaria induces pd1(+)ctla4(+) effector t cells with cell-extrinsic suppressor function
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089727/
https://www.ncbi.nlm.nih.gov/pubmed/27802341
http://dx.doi.org/10.1371/journal.ppat.1005909
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