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Isolation and Analysis of Brain-sequestered Leukocytes from Plasmodium berghei ANKA-infected Mice
Published on: January 2, 2013
Regulatory CD4+ CD25+ Foxp3+ T cells expand during experimental Plasmodium infection but do not prevent cerebral
Ana Margarida Vigário1, Olivier Gorgette, Hélène C Dujardin
1Instituto Gulbenkian de Ciência, 2781-901 Oeiras, Portugal.
Abstract:
Pathogenic CD8+ T cells are implicated in the physiopathological mechanisms leading to experimental cerebral malaria (CM) in Plasmodium berghei ANKA (PbA) infected mice. Therefore, we hypothesised that in CM susceptible mice the neuropathology could be, at least in part, the result of an inefficient control of pathogenic effector T cells by CD4+ CD25+ Treg cells. Remarkably, the number of CD4+ CD25high T cells expressing Foxp3 increased in the spleen during the course of infection. These cells displayed an activated phenotype and consistent with that, CD4+ CD25high Treg cells isolated from PbA-infected mice showed an enhanced regulatory activity in vitro. Surprisingly, these cells do not migrate to the brain at the time of neurological symptoms as the conventional CD4+ T cells do. CM was not exacerbated in anti-CD25 treated mice when infected with PbA one month after treatment, even if splenic CD8+ T cells expressing CD69 increased in these mice. Taken together, these results show that P. berghei infection leads to an increase of the number of splenic CD4+ CD25high Treg cells exhibiting in vitro suppressive function, but they do not seem to be involved in vivo in the protection against CM.
Insights
Pathogenic CD8+ T cells drive experimental cerebral malaria (CM). Despite increased splenic regulatory T cells (Tregs) with enhanced in vitro function during Plasmodium berghei ANKA infection, these Tregs do not migrate to the brain or protect against CM.
Area of Science:
- Immunology
- Infectious Diseases
- Neuroscience
Background:
- Pathogenic CD8+ T cells contribute to experimental cerebral malaria (CM) pathogenesis.
- CD4+ CD25+ regulatory T cells (Tregs) are crucial for controlling immune responses.
Purpose of the Study:
- To investigate the role of CD4+ CD25+ Treg cells in controlling pathogenic effector T cells during experimental cerebral malaria (CM).
- To determine if Treg cells are involved in the neuropathology of CM.
Main Methods:
- Flow cytometry to analyze T cell populations (CD4+, CD8+, CD25+, Foxp3+, CD69+).
- In vitro assays to assess Treg suppressive function.
- Experimental cerebral malaria (CM) induction in mice infected with Plasmodium berghei ANKA (PbA).
- Treatment with anti-CD25 antibodies to deplete Tregs.
Main Results:
- The number of splenic CD4+ CD25high T cells expressing Foxp3 increased during PbA infection.
- These splenic Tregs exhibited enhanced regulatory activity in vitro.
- Tregs did not migrate to the brain during the onset of neurological symptoms.
- CM was not exacerbated in mice depleted of Tregs prior to PbA infection.
Conclusions:
- Plasmodium berghei ANKA infection increases the number and in vitro suppressive function of splenic CD4+ CD25high Treg cells.
- Despite their enhanced in vitro function, these Tregs do not appear to be involved in the in vivo protection against experimental cerebral malaria (CM).
- The neuropathology of CM is not primarily mediated by inefficient Treg control of pathogenic effector T cells.
