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Loss- and Gain-of-Function Approaches Indicate a Dual Role Exerted by Regulatory T Cells in Pulmonary Paracoccidioidomycosis.

Bazan SB, Costa TA, de Araújo EF, Feriotti C, Loures FV, Pretel FD, Calich VL - PLoS Negl Trop Dis (2015)

Bottom Line: Although regulatory T (Treg) cells were shown to control immunity against PCM, deleterious or protective effects were described in different experimental settings.Depletion of Treg cells led to reduced fungal load, diminished pathogen dissemination and increased Th1/Th2/Th17 immunity.Nevertheless, transfer of Treg cells combined with CD4+Foxp3- T cells generated more efficient and balanced immune Th1/Th2/Th17 responses able to limit pathogen growth and excessive tissue inflammation, leading to regressive disease and increased survival rates.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.

ABSTRACT
Paracoccidioidomycosis (PCM), is a pulmonary fungal disease whose severity depends on the adequate development of T cell immunity. Although regulatory T (Treg) cells were shown to control immunity against PCM, deleterious or protective effects were described in different experimental settings. To clarify the function of Treg cells in pulmonary PCM, loss-and gain-of-function approaches were performed with Foxp3GFP knock-in mice and immunodeficient Rag1-/- mice, respectively, which were intratracheally infected with 106 yeast cells. The activity of Foxp3-expressing Treg cells in pulmonary PCM was determined in Foxp3GFP transgenic mice. First, it was verified that natural Treg cells migrate to the lungs of infected mice, where they become activated. Depletion of Treg cells led to reduced fungal load, diminished pathogen dissemination and increased Th1/Th2/Th17 immunity. Further, adoptive transfer of diverse T cell subsets to Rag1-/- mice subsequently infected by the pulmonary route demonstrated that isolated CD4+Foxp3+ Treg cells were able to confer some degree of immunoprotection and that CD4+Foxp3- T cells alone reduced fungal growth and enhanced T cell immunity, but induced vigorous inflammatory reactions in the lungs. Nevertheless, transfer of Treg cells combined with CD4+Foxp3- T cells generated more efficient and balanced immune Th1/Th2/Th17 responses able to limit pathogen growth and excessive tissue inflammation, leading to regressive disease and increased survival rates. Altogether, these loss- and gain-of-function approaches allow us to clearly demonstrate the dual role of Treg cells in pulmonary PCM, their deleterious effects by impairing T cell immunity and pathogen eradication, and their protective role by suppressing exacerbated tissue inflammation.

No MeSH data available.


Related in: MedlinePlus

Histopathological analysis of target organs from infected mice treated with anti-CD25 or control IgG antibodies.(A) Organ micrographs after 2 (top) and 10 (bottom) weeks of infection with P. brasiliensis. Sections were stained with H&E or Grocott and examined with a magnification of 100×. (B) Morphometric analysis of organ lesions from mice treated with anti-CD25 or control IgG after 2 (left) and 10 (right) weeks of infection. Areas were quantified from photomicrographs of organ sections. Data are means ± SD of three independent experiments with similar results (n ≥ 6; ***p < 0.005; ND = not detectable).
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pntd.0004189.g004: Histopathological analysis of target organs from infected mice treated with anti-CD25 or control IgG antibodies.(A) Organ micrographs after 2 (top) and 10 (bottom) weeks of infection with P. brasiliensis. Sections were stained with H&E or Grocott and examined with a magnification of 100×. (B) Morphometric analysis of organ lesions from mice treated with anti-CD25 or control IgG after 2 (left) and 10 (right) weeks of infection. Areas were quantified from photomicrographs of organ sections. Data are means ± SD of three independent experiments with similar results (n ≥ 6; ***p < 0.005; ND = not detectable).

Mentions: Histological examination of organ sections performed after 2 and 10 weeks of infection showed that control mice exhibited more severe pathology, with great number of lesions, granulomas containing augmented numbers of yeast particles and some degree of tissue damage (Fig 4A). By contrast, mice receiving anti-CD25 antibody displayed well preserved lung parenchyma besides reduced amounts of lesions and yeast cells than mice treated with control IgG. Livers and spleens of anti-CD25-treated animals showed normal morphology after 10 weeks of infection, opposite to IgG-treated mice, which showed yeasts-containing granulomas in livers and spleens (Fig 4A). Morphometric analyses performed after 2 and 10 weeks of infection revealed larger lesion areas in the lungs of control mice by week 2, compared with anti-CD25-treated mice (Fig 4B). At week 10 post-infection, IgG-treated animals showed granulomas in the lungs, livers and spleens, contrasting to anti-CD25-trated mice, which exhibited smaller granulomas in the lungs and virtually no lesions in livers and spleens (Fig 4B).


Loss- and Gain-of-Function Approaches Indicate a Dual Role Exerted by Regulatory T Cells in Pulmonary Paracoccidioidomycosis.

Bazan SB, Costa TA, de Araújo EF, Feriotti C, Loures FV, Pretel FD, Calich VL - PLoS Negl Trop Dis (2015)

Histopathological analysis of target organs from infected mice treated with anti-CD25 or control IgG antibodies.(A) Organ micrographs after 2 (top) and 10 (bottom) weeks of infection with P. brasiliensis. Sections were stained with H&E or Grocott and examined with a magnification of 100×. (B) Morphometric analysis of organ lesions from mice treated with anti-CD25 or control IgG after 2 (left) and 10 (right) weeks of infection. Areas were quantified from photomicrographs of organ sections. Data are means ± SD of three independent experiments with similar results (n ≥ 6; ***p < 0.005; ND = not detectable).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4626087&req=5

pntd.0004189.g004: Histopathological analysis of target organs from infected mice treated with anti-CD25 or control IgG antibodies.(A) Organ micrographs after 2 (top) and 10 (bottom) weeks of infection with P. brasiliensis. Sections were stained with H&E or Grocott and examined with a magnification of 100×. (B) Morphometric analysis of organ lesions from mice treated with anti-CD25 or control IgG after 2 (left) and 10 (right) weeks of infection. Areas were quantified from photomicrographs of organ sections. Data are means ± SD of three independent experiments with similar results (n ≥ 6; ***p < 0.005; ND = not detectable).
Mentions: Histological examination of organ sections performed after 2 and 10 weeks of infection showed that control mice exhibited more severe pathology, with great number of lesions, granulomas containing augmented numbers of yeast particles and some degree of tissue damage (Fig 4A). By contrast, mice receiving anti-CD25 antibody displayed well preserved lung parenchyma besides reduced amounts of lesions and yeast cells than mice treated with control IgG. Livers and spleens of anti-CD25-treated animals showed normal morphology after 10 weeks of infection, opposite to IgG-treated mice, which showed yeasts-containing granulomas in livers and spleens (Fig 4A). Morphometric analyses performed after 2 and 10 weeks of infection revealed larger lesion areas in the lungs of control mice by week 2, compared with anti-CD25-treated mice (Fig 4B). At week 10 post-infection, IgG-treated animals showed granulomas in the lungs, livers and spleens, contrasting to anti-CD25-trated mice, which exhibited smaller granulomas in the lungs and virtually no lesions in livers and spleens (Fig 4B).

Bottom Line: Although regulatory T (Treg) cells were shown to control immunity against PCM, deleterious or protective effects were described in different experimental settings.Depletion of Treg cells led to reduced fungal load, diminished pathogen dissemination and increased Th1/Th2/Th17 immunity.Nevertheless, transfer of Treg cells combined with CD4+Foxp3- T cells generated more efficient and balanced immune Th1/Th2/Th17 responses able to limit pathogen growth and excessive tissue inflammation, leading to regressive disease and increased survival rates.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.

ABSTRACT
Paracoccidioidomycosis (PCM), is a pulmonary fungal disease whose severity depends on the adequate development of T cell immunity. Although regulatory T (Treg) cells were shown to control immunity against PCM, deleterious or protective effects were described in different experimental settings. To clarify the function of Treg cells in pulmonary PCM, loss-and gain-of-function approaches were performed with Foxp3GFP knock-in mice and immunodeficient Rag1-/- mice, respectively, which were intratracheally infected with 106 yeast cells. The activity of Foxp3-expressing Treg cells in pulmonary PCM was determined in Foxp3GFP transgenic mice. First, it was verified that natural Treg cells migrate to the lungs of infected mice, where they become activated. Depletion of Treg cells led to reduced fungal load, diminished pathogen dissemination and increased Th1/Th2/Th17 immunity. Further, adoptive transfer of diverse T cell subsets to Rag1-/- mice subsequently infected by the pulmonary route demonstrated that isolated CD4+Foxp3+ Treg cells were able to confer some degree of immunoprotection and that CD4+Foxp3- T cells alone reduced fungal growth and enhanced T cell immunity, but induced vigorous inflammatory reactions in the lungs. Nevertheless, transfer of Treg cells combined with CD4+Foxp3- T cells generated more efficient and balanced immune Th1/Th2/Th17 responses able to limit pathogen growth and excessive tissue inflammation, leading to regressive disease and increased survival rates. Altogether, these loss- and gain-of-function approaches allow us to clearly demonstrate the dual role of Treg cells in pulmonary PCM, their deleterious effects by impairing T cell immunity and pathogen eradication, and their protective role by suppressing exacerbated tissue inflammation.

No MeSH data available.


Related in: MedlinePlus