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

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101291488 Publication Model: eCollection Cited Medium: Internet ISSN: 1935-2735 (Electronic) Linking ISSN: 19352727 NLM ISO Abbreviation: PLoS Negl Trop Dis Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Lung Diseases, Fungal/*immunology ; Paracoccidioidomycosis/*immunology ; T-Lymphocytes, Regulatory/*immunology; Animals ; Artificial Gene Fusion ; Cell Movement ; Forkhead Transcription Factors/genetics ; Green Fluorescent Proteins/analysis ; Green Fluorescent Proteins/genetics ; Lung/immunology ; Lung/pathology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Staining and Labeling/methods ; T-Lymphocyte Subsets/immunology ; T-Lymphocytes, Regulatory/chemistry

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.

Br J Exp Pathol. 1985 Oct;66(5):585-94. (PMID: 4063162)
Rev Inst Med Trop Sao Paulo. 1969 May-Jun;11(3):177-81. (PMID: 5824780)
J Med Vet Mycol. 1992;30(3):261-4. (PMID: 1517962)
Infect Immun. 1995 May;63(5):1777-83. (PMID: 7729885)
Immunity. 2005 Mar;22(3):329-41. (PMID: 15780990)
Nat Immunol. 2005 Apr;6(4):353-60. (PMID: 15785761)
Nat Immunol. 2005 Nov;6(11):1142-51. (PMID: 16227984)
J Immunol. 2006 Nov 1;177(9):5811-8. (PMID: 17056505)
J Immunol. 2006 Nov 1;177(9):6215-26. (PMID: 17056551)
J Exp Med. 2006 Oct 30;203(11):2451-60. (PMID: 17015634)
J Immunol. 2007 Mar 1;178(5):2661-5. (PMID: 17312107)
J Exp Med. 2007 Sep 3;204(9):2159-69. (PMID: 17709423)
J Immunol. 2008 Mar 1;180(5):3049-56. (PMID: 18292527)
J Immunol. 2009 Apr 1;182(7):3985-94. (PMID: 19299696)
J Immunol. 2009 Jul 15;183(2):1279-90. (PMID: 19553529)
Med Mycol. 2009 Nov;47(7):722-33. (PMID: 19888805)
J Biomed Biotechnol. 2010;2010:786078. (PMID: 20037737)
Infect Immun. 2010 Mar;78(3):1078-88. (PMID: 20008536)
Eur J Immunol. 2010 Mar;40(3):780-6. (PMID: 20039297)
J Immunol. 2010 May 1;184(9):5224-31. (PMID: 20335531)
PLoS Pathog. 2010;6(8):e1001043. (PMID: 20714351)
Infect Immun. 2010 Nov;78(11):4922-35. (PMID: 20713624)
Immunity. 2011 Mar 25;34(3):422-34. (PMID: 21435589)
PLoS One. 2011;6(11):e27849. (PMID: 22125630)
Immunology. 2012 May;136(1):1-10. (PMID: 22211994)
J Exp Med. 2012 Sep 24;209(10):1713-22, S1-19. (PMID: 22966003)
PLoS One. 2012;7(11):e51071. (PMID: 23226464)
Int J Clin Exp Pathol. 2013;6(2):116-23. (PMID: 23329997)
PLoS One. 2013;8(1):e54845. (PMID: 23382985)
Trends Mol Med. 2013 Jun;19(6):355-67. (PMID: 23601906)
PLoS Negl Trop Dis. 2013;7(10):e2512. (PMID: 24205424)
J Leukoc Biol. 2014 Jul;96(1):39-48. (PMID: 24744433)
J Infect Dis. 2014 Sep 1;210(5):762-73. (PMID: 24604821)
J Immunol. 2010 Aug 15;185(4):2382-92. (PMID: 20639494)
Eur J Immunol. 2002 May;32(5):1282-91. (PMID: 11981815)
Clin Immunol. 2002 May;103(2):185-95. (PMID: 12027424)
J Immunol. 2002 Dec 1;169(11):6298-308. (PMID: 12444136)
J Immunol. 2004 Apr 1;172(7):4123-32. (PMID: 15034024)
Mycopathologia. 1990 Sep;111(3):173-80. (PMID: 2233986)

0 (Forkhead Transcription Factors)
0 (Foxp3 protein, mouse)
147336-22-9 (Green Fluorescent Proteins)

Date Created: 20151030 Date Completed: 20160328 Latest Revision: 20190202

20240829

PMC4626087

10.1371/journal.pntd.0004189

26512987