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IL-10 from CD4CD25Foxp3CD127 adaptive regulatory T cells modulates parasite clearance and pathology during malaria infection.

Couper KN, Blount DG, Wilson MS, Hafalla JC, Belkaid Y, Kamanaka M, Flavell RA, de Souza JB, Riley EM - PLoS Pathog. (2008)

Bottom Line: Failure to develop an effective pro-inflammatory response can lead to unrestricted parasite replication, whilst failure to regulate this response leads to the development of severe immunopathology.IL-10 and TGF-beta are known to be important components of the regulatory response, but the cellular source of these cytokines is still unknown.In contrast, we find that adaptive IL-10-producing, CD4+ T cells (which are CD25-, Foxp3-, and CD127- and do not produce Th1, Th2, or Th17 associated cytokines) that are generated during both PyL and non-lethal P. yoelii 17X (PyNL) infections are able to down-regulate pro-inflammatory responses and impede parasite clearance.

View Article: PubMed Central - PubMed

Affiliation: Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.

ABSTRACT
The outcome of malaria infection is determined, in part, by the balance of pro-inflammatory and regulatory immune responses. Failure to develop an effective pro-inflammatory response can lead to unrestricted parasite replication, whilst failure to regulate this response leads to the development of severe immunopathology. IL-10 and TGF-beta are known to be important components of the regulatory response, but the cellular source of these cytokines is still unknown. Here we have examined the role of natural and adaptive regulatory T cells in the control of malaria infection and find that classical CD4+CD25(hi) (and Foxp3+) regulatory T cells do not significantly influence the outcome of infections with the lethal (17XL) strain of Plasmodium yoelii (PyL). In contrast, we find that adaptive IL-10-producing, CD4+ T cells (which are CD25-, Foxp3-, and CD127- and do not produce Th1, Th2, or Th17 associated cytokines) that are generated during both PyL and non-lethal P. yoelii 17X (PyNL) infections are able to down-regulate pro-inflammatory responses and impede parasite clearance. In summary, we have identified a population of induced Foxp3- regulatory (Tr1) T cells, characterised by production of IL-10 and down regulation of IL-7Ralpha, that modulates the inflammatory response to malaria.

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Course of infection of lethal (PyL) and non-lethal (PyNL) P. yoelii in C57BL/6 mice.C57BL/6 mice were infected i.v. with 104 P. yoelii 17XL (PyL) or P. yoelii 17X (PyNL) parasites. The course of each infection was followed by monitoring (A) parasitaemia, (B) survival and(C) anaemia. 4–5 mice per group. Results are representative of 4 separate experiments. * = significant differences (p<0.05) between PyL and PyNL.
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ppat-1000004-g001: Course of infection of lethal (PyL) and non-lethal (PyNL) P. yoelii in C57BL/6 mice.C57BL/6 mice were infected i.v. with 104 P. yoelii 17XL (PyL) or P. yoelii 17X (PyNL) parasites. The course of each infection was followed by monitoring (A) parasitaemia, (B) survival and(C) anaemia. 4–5 mice per group. Results are representative of 4 separate experiments. * = significant differences (p<0.05) between PyL and PyNL.

Mentions: In accordance with previous observations [5],[22], infection of C57BL/6 mice with 104 P. yoelii 17XL (PyL) parasites was associated with a rapid onset of fulminant parasitaemia (approaching 100% by day 7 pi) that was universally fatal (Figure 1A, B). In contrast, infection with 104 P. yoelii 17X (NL) (PyNL) parasites led to a more gradual increase in parasitaemia with peak parasitaemia of approx. 30% on day 14 pi, before the infection eventually resolved. Significant differences in malaria-induced anaemia were also evident between lethal and non-lethal infections, with more rapid onset and increased severity of anaemia occurring in PyL-infected mice compared with PyNL-infected mice (Figure 1C).


IL-10 from CD4CD25Foxp3CD127 adaptive regulatory T cells modulates parasite clearance and pathology during malaria infection.

Couper KN, Blount DG, Wilson MS, Hafalla JC, Belkaid Y, Kamanaka M, Flavell RA, de Souza JB, Riley EM - PLoS Pathog. (2008)

Course of infection of lethal (PyL) and non-lethal (PyNL) P. yoelii in C57BL/6 mice.C57BL/6 mice were infected i.v. with 104 P. yoelii 17XL (PyL) or P. yoelii 17X (PyNL) parasites. The course of each infection was followed by monitoring (A) parasitaemia, (B) survival and(C) anaemia. 4–5 mice per group. Results are representative of 4 separate experiments. * = significant differences (p<0.05) between PyL and PyNL.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2291447&req=5

ppat-1000004-g001: Course of infection of lethal (PyL) and non-lethal (PyNL) P. yoelii in C57BL/6 mice.C57BL/6 mice were infected i.v. with 104 P. yoelii 17XL (PyL) or P. yoelii 17X (PyNL) parasites. The course of each infection was followed by monitoring (A) parasitaemia, (B) survival and(C) anaemia. 4–5 mice per group. Results are representative of 4 separate experiments. * = significant differences (p<0.05) between PyL and PyNL.
Mentions: In accordance with previous observations [5],[22], infection of C57BL/6 mice with 104 P. yoelii 17XL (PyL) parasites was associated with a rapid onset of fulminant parasitaemia (approaching 100% by day 7 pi) that was universally fatal (Figure 1A, B). In contrast, infection with 104 P. yoelii 17X (NL) (PyNL) parasites led to a more gradual increase in parasitaemia with peak parasitaemia of approx. 30% on day 14 pi, before the infection eventually resolved. Significant differences in malaria-induced anaemia were also evident between lethal and non-lethal infections, with more rapid onset and increased severity of anaemia occurring in PyL-infected mice compared with PyNL-infected mice (Figure 1C).

Bottom Line: Failure to develop an effective pro-inflammatory response can lead to unrestricted parasite replication, whilst failure to regulate this response leads to the development of severe immunopathology.IL-10 and TGF-beta are known to be important components of the regulatory response, but the cellular source of these cytokines is still unknown.In contrast, we find that adaptive IL-10-producing, CD4+ T cells (which are CD25-, Foxp3-, and CD127- and do not produce Th1, Th2, or Th17 associated cytokines) that are generated during both PyL and non-lethal P. yoelii 17X (PyNL) infections are able to down-regulate pro-inflammatory responses and impede parasite clearance.

View Article: PubMed Central - PubMed

Affiliation: Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.

ABSTRACT
The outcome of malaria infection is determined, in part, by the balance of pro-inflammatory and regulatory immune responses. Failure to develop an effective pro-inflammatory response can lead to unrestricted parasite replication, whilst failure to regulate this response leads to the development of severe immunopathology. IL-10 and TGF-beta are known to be important components of the regulatory response, but the cellular source of these cytokines is still unknown. Here we have examined the role of natural and adaptive regulatory T cells in the control of malaria infection and find that classical CD4+CD25(hi) (and Foxp3+) regulatory T cells do not significantly influence the outcome of infections with the lethal (17XL) strain of Plasmodium yoelii (PyL). In contrast, we find that adaptive IL-10-producing, CD4+ T cells (which are CD25-, Foxp3-, and CD127- and do not produce Th1, Th2, or Th17 associated cytokines) that are generated during both PyL and non-lethal P. yoelii 17X (PyNL) infections are able to down-regulate pro-inflammatory responses and impede parasite clearance. In summary, we have identified a population of induced Foxp3- regulatory (Tr1) T cells, characterised by production of IL-10 and down regulation of IL-7Ralpha, that modulates the inflammatory response to malaria.

Show MeSH
Related in: MedlinePlus