학술논문
Acute Malaria Induces PD1.sup.+CTLA4.sup.+ Effector T Cells with Cell-Extrinsic Suppressor Function
Research Article
Research Article
Document Type
Report
Author
Source
PLoS Pathogens. November 1, 2016, Vol. 12 Issue 11, e1005909
Subject
Language
English
ISSN
1553-7366
Abstract
Author(s): Maria Sophia Mackroth 1,2,*, Annemieke Abel 2, Christiane Steeg 2, Julian Schulze zur Wiesch 1, Thomas Jacobs 2 Introduction Malaria remains one of the leading health burdens worldwide with [...]
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.sup.+ 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.sup.+ 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.sup.+ CTLA4.sup.+ CD4.sup.+ T cells that simultaneously produced IFN[gamma] and IL10. This antigen-specific cytokine production was enhanced by blocking PD1/PDL1 and CTLA4. PD1.sup.+ CTLA4.sup.+ CD4.sup.+ T cells were further isolated based on surface expression of PD1 and their inhibitory function investigated in-vitro. Isolated PD1.sup.+ CTLA4.sup.+ CD4.sup.+ T cells suppressed the proliferation of the total CD4.sup.+ 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.sup.+ CTLA4.sup.+ CD4.sup.+ T.sub.effector cells that coproduce IFN[gamma] and IL10, and inhibit other CD4.sup.+ T cells. Transient induction of regulatory T.sub.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.
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.sup.+ 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.sup.+ 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.sup.+ CTLA4.sup.+ CD4.sup.+ T cells that simultaneously produced IFN[gamma] and IL10. This antigen-specific cytokine production was enhanced by blocking PD1/PDL1 and CTLA4. PD1.sup.+ CTLA4.sup.+ CD4.sup.+ T cells were further isolated based on surface expression of PD1 and their inhibitory function investigated in-vitro. Isolated PD1.sup.+ CTLA4.sup.+ CD4.sup.+ T cells suppressed the proliferation of the total CD4.sup.+ 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.sup.+ CTLA4.sup.+ CD4.sup.+ T.sub.effector cells that coproduce IFN[gamma] and IL10, and inhibit other CD4.sup.+ T cells. Transient induction of regulatory T.sub.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.