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

CD127low Foxp3− CD4+ T cells that do not constitutively express CD25 are the major source of IL-10 during P. yoelii infection.Transgenic, IL-10-GFP knockin tiger mice were infected with PyL or PyNL. (A) Splenic lymphocytes from infected or uninfected control mice were analysed for expression of CD4+ and GFP. (B,C) 7 days post infection, splenic CD4+ T cells were analysed for (B) expression of CD25 and Foxp3, or (C) GFP (IL-10) and CD25, CD69, CD62L or CD127. (D) The frequency and number of GFP+ (IL-10+) CD4+ T cells was calculated 7 days post infection in infected or uninfected mice. Groups consisted of 3–5 mice and the results are representative of 2 independent experiments.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2291447&req=5

ppat-1000004-g005: CD127low Foxp3− CD4+ T cells that do not constitutively express CD25 are the major source of IL-10 during P. yoelii infection.Transgenic, IL-10-GFP knockin tiger mice were infected with PyL or PyNL. (A) Splenic lymphocytes from infected or uninfected control mice were analysed for expression of CD4+ and GFP. (B,C) 7 days post infection, splenic CD4+ T cells were analysed for (B) expression of CD25 and Foxp3, or (C) GFP (IL-10) and CD25, CD69, CD62L or CD127. (D) The frequency and number of GFP+ (IL-10+) CD4+ T cells was calculated 7 days post infection in infected or uninfected mice. Groups consisted of 3–5 mice and the results are representative of 2 independent experiments.

Mentions: To more accurately determine the cellular source of IL-10 during P. yoelii infection, splenocytes from IL-10-GFP reporter mice [21] were examined for expression of GFP and various cell surface markers on selected days after PyL or PyNL infection (Figure 5A–C). In both infections, from day 5 onwards, the vast majority of the IL-10+ cells were CD4+ lymphocytes. At no point during either PyL or PyNL infection did we observe significant IL-10 production by myeloid (CD11b+), lymphoid dendritic cells (CD11c+) or macrophages (F4-80+) (results not shown). IL-10 production by CD19+ B cells was observed, on day 7 post-infection, only during PyL but not PyNL infection (results not shown). Moreover, IL-10 producing non-CD4+ T cells produced only low quantities of IL-10, whereas CD4+ T cells were heterogeneous in their ability to produce IL-10 (Figure 5A).


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)

CD127low Foxp3− CD4+ T cells that do not constitutively express CD25 are the major source of IL-10 during P. yoelii infection.Transgenic, IL-10-GFP knockin tiger mice were infected with PyL or PyNL. (A) Splenic lymphocytes from infected or uninfected control mice were analysed for expression of CD4+ and GFP. (B,C) 7 days post infection, splenic CD4+ T cells were analysed for (B) expression of CD25 and Foxp3, or (C) GFP (IL-10) and CD25, CD69, CD62L or CD127. (D) The frequency and number of GFP+ (IL-10+) CD4+ T cells was calculated 7 days post infection in infected or uninfected mice. Groups consisted of 3–5 mice and the results are representative of 2 independent experiments.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1000004-g005: CD127low Foxp3− CD4+ T cells that do not constitutively express CD25 are the major source of IL-10 during P. yoelii infection.Transgenic, IL-10-GFP knockin tiger mice were infected with PyL or PyNL. (A) Splenic lymphocytes from infected or uninfected control mice were analysed for expression of CD4+ and GFP. (B,C) 7 days post infection, splenic CD4+ T cells were analysed for (B) expression of CD25 and Foxp3, or (C) GFP (IL-10) and CD25, CD69, CD62L or CD127. (D) The frequency and number of GFP+ (IL-10+) CD4+ T cells was calculated 7 days post infection in infected or uninfected mice. Groups consisted of 3–5 mice and the results are representative of 2 independent experiments.
Mentions: To more accurately determine the cellular source of IL-10 during P. yoelii infection, splenocytes from IL-10-GFP reporter mice [21] were examined for expression of GFP and various cell surface markers on selected days after PyL or PyNL infection (Figure 5A–C). In both infections, from day 5 onwards, the vast majority of the IL-10+ cells were CD4+ lymphocytes. At no point during either PyL or PyNL infection did we observe significant IL-10 production by myeloid (CD11b+), lymphoid dendritic cells (CD11c+) or macrophages (F4-80+) (results not shown). IL-10 production by CD19+ B cells was observed, on day 7 post-infection, only during PyL but not PyNL infection (results not shown). Moreover, IL-10 producing non-CD4+ T cells produced only low quantities of IL-10, whereas CD4+ T cells were heterogeneous in their ability to produce IL-10 (Figure 5A).

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