PMID- 26512987
OWN - NLM
STAT- MEDLINE
DCOM- 20160328
LR  - 20190202
IS  - 1935-2735 (Electronic)
IS  - 1935-2727 (Print)
IS  - 1935-2727 (Linking)
VI  - 9
IP  - 10
DP  - 2015
TI  - Loss- and Gain-of-Function Approaches Indicate a Dual Role Exerted by Regulatory 
      T Cells in Pulmonary Paracoccidioidomycosis.
PG  - e0004189
LID - 10.1371/journal.pntd.0004189 [doi]
LID - e0004189
AB  - 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.
FAU - Bazan, Silvia B
AU  - Bazan SB
AD  - Departamento de Imunologia, Instituto de Ciencias Biomedicas, Universidade de Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Costa, Tania A
AU  - Costa TA
AD  - Departamento de Imunologia, Instituto de Ciencias Biomedicas, Universidade de Sao 
      Paulo, Sao Paulo, Brazil.
FAU - de Araujo, Eliseu Frank
AU  - de Araujo EF
AD  - Departamento de Imunologia, Instituto de Ciencias Biomedicas, Universidade de Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Feriotti, Claudia
AU  - Feriotti C
AD  - Departamento de Imunologia, Instituto de Ciencias Biomedicas, Universidade de Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Loures, Flavio V
AU  - Loures FV
AD  - Departamento de Imunologia, Instituto de Ciencias Biomedicas, Universidade de Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Pretel, Fernando D
AU  - Pretel FD
AD  - Centro de Facilidades de Apoio a Pesquisa (CEFAP), Instituto de Ciencias 
      Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brazil.
FAU - Calich, Vera L G
AU  - Calich VL
AD  - Departamento de Imunologia, Instituto de Ciencias Biomedicas, Universidade de Sao 
      Paulo, Sao Paulo, Brazil.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151029
PL  - United States
TA  - PLoS Negl Trop Dis
JT  - PLoS neglected tropical diseases
JID - 101291488
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Foxp3 protein, mouse)
RN  - 147336-22-9 (Green Fluorescent Proteins)
SB  - IM
MH  - Animals
MH  - Artificial Gene Fusion
MH  - Cell Movement
MH  - Forkhead Transcription Factors/genetics
MH  - Green Fluorescent Proteins/analysis/genetics
MH  - Lung/immunology/pathology
MH  - Lung Diseases, Fungal/*immunology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Paracoccidioidomycosis/*immunology
MH  - Staining and Labeling/methods
MH  - T-Lymphocyte Subsets/immunology
MH  - T-Lymphocytes, Regulatory/chemistry/*immunology
PMC - PMC4626087
COIS- The authors have declared that no competing interests exist.
EDAT- 2015/10/30 06:00
MHDA- 2016/03/29 06:00
PMCR- 2015/10/29
CRDT- 2015/10/30 06:00
PHST- 2015/08/04 00:00 [received]
PHST- 2015/10/02 00:00 [accepted]
PHST- 2015/10/30 06:00 [entrez]
PHST- 2015/10/30 06:00 [pubmed]
PHST- 2016/03/29 06:00 [medline]
PHST- 2015/10/29 00:00 [pmc-release]
AID - PNTD-D-15-01368 [pii]
AID - 10.1371/journal.pntd.0004189 [doi]
PST - epublish
SO  - PLoS Negl Trop Dis. 2015 Oct 29;9(10):e0004189. doi: 
      10.1371/journal.pntd.0004189. eCollection 2015.