Article
CD4+CTLA-4+PD-1+ T effector cells modulate the T cell response during malaria
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Authors
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Maria Mackroth
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany; University Hospital Hamburg Eppendorf, Hamburg, Germany
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Christiane Steeg
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany; University Hospital Hamburg Eppendorf, Hamburg, Germany
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Annemieke Abel
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany; University Hospital Hamburg Eppendorf, Hamburg, Germany
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Julian Schulze zur Wiesch
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany; University Hospital Hamburg Eppendorf, Hamburg, Germany
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Thomas Jacobs
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany; University Hospital Hamburg Eppendorf, Hamburg, Germany
| Published: | December 17, 2014 |
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Outline
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Malaria, caused by infection with Plasmodium falciparum (Pf), can progress to severe disease with high lethality. Observations from studies in malaria-endemic areas and in murine malaria models indicate that a strong pro-inflammatory T cell response contributes to severe malaria. An optimal regulation of T effector cells (Teff cells) is therefore crucial to control parasitaemia while preventing immunpathology. In several infectious diseases, the pro-inflammatory response is counter-balanced through the expression of co-inhibitory receptors such as CTLA-4 and PD-1 on T cells but their role in the immune response in malaria remains poorly understood.
We hypothesized that acute malaria leads to induction of co-inhibitory receptors, which modulate T cell function during infection.
Spleen cells from P. berghei infected mice or blood samples obtained from patients with acute malaria were analyzed for the expression of co-inhibitory receptors and ligands using flow cytometry. In both, rodent as wells as human malaria, the co-inhibitory receptors CTLA-4 and PD-1 are strongly induced on Teff cells and their ligands are upregulated on monocytes, B-cells and T cells. In-vitro stimulation revealed a distinct population of CTLA-4+PD-1+ CD4+ T cells that simultaneously produced IFN-γ and IL10.
We further isolated CD4+ T cells subsets based on the surface expression of CTLA-4 and PD-1 and investigated their inhibitory function on naïve CD4+ T cells after stimulation with anti-CD3. CTLA-4+PD-1+ T cells displayed a dose-dependent suppression of T cell proliferation in a cell-extrinisic manner, which was even stronger than conventional Treg.
In summary, malaria leads to induction of antigen-specific Teff cells with high expression of CTLA-4 and PD-1, which co-produce IFN-γ and IL10 while inhibiting CD4+ T cell proliferation in trans. Regulation by CD4+ Teff cells might be an important mechanism to control T cell responses and prevent severe inflammation in acute malaria and potentially other infectious diseases.
