Limits...
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.

Show MeSH

Related in: MedlinePlus

IL-10 producing CD4+ T cells that develop during P. yoelii infection are Tr1 cells and not Th1, Th2, or Th17 cells.Splenic CD4+ T cells were isolated from transgenic IL-10-GFP mice on day 7 of PyL or PyNL infection and were purified by flow cytometric cell sorting into GFP+ (IL-10+) and GFP− (IL-10−) populations. (A) shows the purity of the purified GFP+ and GFP− populations. (B) Expression of IL-10, Foxp3, IFN-γ, IL-4, IL-13 and IL-17A mRNA was determined by real time PCR (Taqman) relative to the house keeping gene, GAPDH. The results are shown as the fold change in expression relative to uninfected naïve CD4+ T cells. For Taqman analysis, purified cells from several mice in each group were pooled.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2291447&req=5

ppat-1000004-g006: IL-10 producing CD4+ T cells that develop during P. yoelii infection are Tr1 cells and not Th1, Th2, or Th17 cells.Splenic CD4+ T cells were isolated from transgenic IL-10-GFP mice on day 7 of PyL or PyNL infection and were purified by flow cytometric cell sorting into GFP+ (IL-10+) and GFP− (IL-10−) populations. (A) shows the purity of the purified GFP+ and GFP− populations. (B) Expression of IL-10, Foxp3, IFN-γ, IL-4, IL-13 and IL-17A mRNA was determined by real time PCR (Taqman) relative to the house keeping gene, GAPDH. The results are shown as the fold change in expression relative to uninfected naïve CD4+ T cells. For Taqman analysis, purified cells from several mice in each group were pooled.

Mentions: We have shown that CD4+ T cells are the primary source of IL-10 during malaria infection, and that these cells do not express CD25, suggesting that they may not be conventional nTreg cells. Since IL-10 can be produced by various effector CD4+ T cell subsets (including Th1, Th2 and Th17 cells), as well as specialised regulatory populations such as Tr1 [19, 20 34–36], we examined the expression of Th1, Th2 and Th17 lineage-associated cytokines in IL-10-producing (GFP+) and IL-10-GFP− CD4+ T cells purified from IL-10-GFP reporter mice on day 7 of infection. As seen previously (Figure 5), GFP expression was similar in CD4+ T cells isolated from PyL and PyNL infected mice (Figure 6A). As expected, IL-10 mRNA was expressed at much higher levels in GFP+ than in GFP− cells but cells isolated from PyL and PyNL infected animals expressed similar levels of IL-10 mRNA (Figure 6B). Importantly, Foxp3 mRNA was not upregulated in IL-10-GFP+ cells isolated during either PyL or PyNL infection, confirming that the IL-10-producing CD4+ T cells that develop during P. yoelii infection are neither natural nor induced Foxp3+ regulatory T cells. Moreover, GFP+ cells did not express significant amounts of mRNA for IFN-γ, IL-4 or IL-17, thus distinguishing them from classical Th1, Th2 and Th17 cells. Although IL-10-GFP+ cells expressed IL-13 mRNA, levels were comparable to those seen in GFP− cells indicating that IL-10 producing cells did not preferentially co-produce IL-13. Thus, the IL-10-producing CD4+ T cells induced during P. yoelii infection fit the definition [35] of adaptive, Tr1, regulatory T cells.


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 producing CD4+ T cells that develop during P. yoelii infection are Tr1 cells and not Th1, Th2, or Th17 cells.Splenic CD4+ T cells were isolated from transgenic IL-10-GFP mice on day 7 of PyL or PyNL infection and were purified by flow cytometric cell sorting into GFP+ (IL-10+) and GFP− (IL-10−) populations. (A) shows the purity of the purified GFP+ and GFP− populations. (B) Expression of IL-10, Foxp3, IFN-γ, IL-4, IL-13 and IL-17A mRNA was determined by real time PCR (Taqman) relative to the house keeping gene, GAPDH. The results are shown as the fold change in expression relative to uninfected naïve CD4+ T cells. For Taqman analysis, purified cells from several mice in each group were pooled.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1000004-g006: IL-10 producing CD4+ T cells that develop during P. yoelii infection are Tr1 cells and not Th1, Th2, or Th17 cells.Splenic CD4+ T cells were isolated from transgenic IL-10-GFP mice on day 7 of PyL or PyNL infection and were purified by flow cytometric cell sorting into GFP+ (IL-10+) and GFP− (IL-10−) populations. (A) shows the purity of the purified GFP+ and GFP− populations. (B) Expression of IL-10, Foxp3, IFN-γ, IL-4, IL-13 and IL-17A mRNA was determined by real time PCR (Taqman) relative to the house keeping gene, GAPDH. The results are shown as the fold change in expression relative to uninfected naïve CD4+ T cells. For Taqman analysis, purified cells from several mice in each group were pooled.
Mentions: We have shown that CD4+ T cells are the primary source of IL-10 during malaria infection, and that these cells do not express CD25, suggesting that they may not be conventional nTreg cells. Since IL-10 can be produced by various effector CD4+ T cell subsets (including Th1, Th2 and Th17 cells), as well as specialised regulatory populations such as Tr1 [19, 20 34–36], we examined the expression of Th1, Th2 and Th17 lineage-associated cytokines in IL-10-producing (GFP+) and IL-10-GFP− CD4+ T cells purified from IL-10-GFP reporter mice on day 7 of infection. As seen previously (Figure 5), GFP expression was similar in CD4+ T cells isolated from PyL and PyNL infected mice (Figure 6A). As expected, IL-10 mRNA was expressed at much higher levels in GFP+ than in GFP− cells but cells isolated from PyL and PyNL infected animals expressed similar levels of IL-10 mRNA (Figure 6B). Importantly, Foxp3 mRNA was not upregulated in IL-10-GFP+ cells isolated during either PyL or PyNL infection, confirming that the IL-10-producing CD4+ T cells that develop during P. yoelii infection are neither natural nor induced Foxp3+ regulatory T cells. Moreover, GFP+ cells did not express significant amounts of mRNA for IFN-γ, IL-4 or IL-17, thus distinguishing them from classical Th1, Th2 and Th17 cells. Although IL-10-GFP+ cells expressed IL-13 mRNA, levels were comparable to those seen in GFP− cells indicating that IL-10 producing cells did not preferentially co-produce IL-13. Thus, the IL-10-producing CD4+ T cells induced during P. yoelii infection fit the definition [35] of adaptive, Tr1, regulatory T cells.

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