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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 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.

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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IL-10 ameliorates hepatic pathology during PyL and PyNL infection.Liver pathology was examined (A) in WT and IL-10−/− mice that were either uninfected or had been infected with P. yoelii 7 days (PyL, PyNL) or 14 days (PyNL) previously, (B) on day 25 post-infection with PyNL in RAG-1−/− mice reconstituted with either WT or IL-10−/− CD4+ T cells prior to infection. Groups consisted of 4–5 mice and the slides shown are representative of mice from 2 independent experiments. Arrows highlight areas of interest: c = central vein periportal infiltration, pv = vessels packed with inflammatory cells, p = pigmented kupffer cells, n = necrosis, i = inflammation in parenchymia, pt = necrosis and gross infiltration in portal triad.
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ppat-1000004-g009: IL-10 ameliorates hepatic pathology during PyL and PyNL infection.Liver pathology was examined (A) in WT and IL-10−/− mice that were either uninfected or had been infected with P. yoelii 7 days (PyL, PyNL) or 14 days (PyNL) previously, (B) on day 25 post-infection with PyNL in RAG-1−/− mice reconstituted with either WT or IL-10−/− CD4+ T cells prior to infection. Groups consisted of 4–5 mice and the slides shown are representative of mice from 2 independent experiments. Arrows highlight areas of interest: c = central vein periportal infiltration, pv = vessels packed with inflammatory cells, p = pigmented kupffer cells, n = necrosis, i = inflammation in parenchymia, pt = necrosis and gross infiltration in portal triad.

Mentions: Histopathological examination of infected animals did not reveal any liver or lung damage 3 days post-infection (data not shown) but revealed significantly more hepatic cellular changes including periportal inflammation, necrosis and bridging necrosis in IL-10−/− mice than in WT mice on days 7 and 14 post-infection (Figure 9A) and this was significantly more severe in PyL-infected than PyNL-infected animals on day 7 post-infection. We also found that by day 25 of PyNL infection, RAG−/− recipients of IL-10−/− CD4+ T cells had developed significantly more severe hepatic periportal inflammation and necrosis (including bridging necrosis) than RAG−/− recipients of WT CD4+ T cells (Figure 9B). Thus, T cell derived IL-10, although negatively regulating parasite killing, is protective during malaria infection by preventing the onset of immunopathology.


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)

IL-10 ameliorates hepatic pathology during PyL and PyNL infection.Liver pathology was examined (A) in WT and IL-10−/− mice that were either uninfected or had been infected with P. yoelii 7 days (PyL, PyNL) or 14 days (PyNL) previously, (B) on day 25 post-infection with PyNL in RAG-1−/− mice reconstituted with either WT or IL-10−/− CD4+ T cells prior to infection. Groups consisted of 4–5 mice and the slides shown are representative of mice from 2 independent experiments. Arrows highlight areas of interest: c = central vein periportal infiltration, pv = vessels packed with inflammatory cells, p = pigmented kupffer cells, n = necrosis, i = inflammation in parenchymia, pt = necrosis and gross infiltration in portal triad.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2291447&req=5

ppat-1000004-g009: IL-10 ameliorates hepatic pathology during PyL and PyNL infection.Liver pathology was examined (A) in WT and IL-10−/− mice that were either uninfected or had been infected with P. yoelii 7 days (PyL, PyNL) or 14 days (PyNL) previously, (B) on day 25 post-infection with PyNL in RAG-1−/− mice reconstituted with either WT or IL-10−/− CD4+ T cells prior to infection. Groups consisted of 4–5 mice and the slides shown are representative of mice from 2 independent experiments. Arrows highlight areas of interest: c = central vein periportal infiltration, pv = vessels packed with inflammatory cells, p = pigmented kupffer cells, n = necrosis, i = inflammation in parenchymia, pt = necrosis and gross infiltration in portal triad.
Mentions: Histopathological examination of infected animals did not reveal any liver or lung damage 3 days post-infection (data not shown) but revealed significantly more hepatic cellular changes including periportal inflammation, necrosis and bridging necrosis in IL-10−/− mice than in WT mice on days 7 and 14 post-infection (Figure 9A) and this was significantly more severe in PyL-infected than PyNL-infected animals on day 7 post-infection. We also found that by day 25 of PyNL infection, RAG−/− recipients of IL-10−/− CD4+ T cells had developed significantly more severe hepatic periportal inflammation and necrosis (including bridging necrosis) than RAG−/− recipients of WT CD4+ T cells (Figure 9B). Thus, T cell derived IL-10, although negatively regulating parasite killing, is protective during malaria infection by preventing the onset of immunopathology.

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 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.

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