FoxP3 provides competitive fitness to CD4⁺CD25⁺ T cells in leprosy patients via transcriptional regulation

Sudhir Kumar; Raza Ali Naqvi; Riyasat Ali; Richa Rani; Neena Khanna; D N Rao

doi:10.1002/eji.201343649

FoxP3 provides competitive fitness to CD4⁺CD25⁺ T cells in leprosy patients via transcriptional regulation

Eur J Immunol. 2014 Feb;44(2):431-9. doi: 10.1002/eji.201343649. Epub 2013 Dec 4.

Authors

Sudhir Kumar¹, Raza Ali Naqvi, Riyasat Ali, Richa Rani, Neena Khanna, D N Rao

Affiliation

¹ Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi, India.

PMID: 24214631
DOI: 10.1002/eji.201343649

Abstract

Leprosy is a chronic infectious disease caused by Mycobacterium leprae. FoxP3 have been shown to have important implications in various diseases. The present study describes the mechanism of action of FoxP3 in CD4⁺CD25⁺ T cells derived from leprosy patients. Increased molecular interactions of FoxP3 with histone deacetylases 7/9 in the nucleus of CD4⁺CD25⁺ T cells derived from borderline lepromatous leprosy/lepromatous leprosy (BL/LL) patients were found to be responsible for FoxP3-driven immune suppression activities during the progression of leprosy. Further, downregulation of CTLA-4 and CD25 genes in siFoxP3-treated PBMCs derived from BL/LL patients elucidated the transcription-activating nature of FoxP3. This observation was supported by direct binding of FoxP3 to the promoter region of the CTLA-4 and CD25 genes, and FoxP3's molecular interaction with histone acetyl transferases. The study also revealed that the increased expression of miR155 in CD4⁺CD25⁺ cells from BL/LL governs the competitive fitness of these cells. Again, reduced Annexin V & propidium iodide staining and Nur77 expression, and concomitantly increased Ki-67 positivity suggested that CD4⁺CD25⁺ cells derived from BL/LL patients are more competitively fit than those from borderline tuberculoid leprosy/tuberculoid leprosy and healthy controls. Taken together, the study shows the orchestration of FoxP3 leading to competitive fitness of Treg cells in leprosy.

Keywords: Competitive fitness; FoxP3; HDAC7; HDAC9; Histone acetyl transferase; Leprosy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
CD4-Positive T-Lymphocytes / immunology*
CD4-Positive T-Lymphocytes / metabolism
CTLA-4 Antigen / genetics
CTLA-4 Antigen / immunology
CTLA-4 Antigen / metabolism
Cell Proliferation
Cell Survival / genetics
Cell Survival / immunology
Female
Forkhead Transcription Factors / genetics*
Forkhead Transcription Factors / immunology
Forkhead Transcription Factors / metabolism
Gene Expression Regulation / genetics*
Gene Expression Regulation / immunology
Histone Deacetylases / genetics
Histone Deacetylases / immunology
Histone Deacetylases / metabolism
Humans
Interleukin-2 / genetics
Interleukin-2 / immunology
Interleukin-2 / metabolism
Interleukin-2 Receptor alpha Subunit / genetics*
Interleukin-2 Receptor alpha Subunit / immunology
Interleukin-2 Receptor alpha Subunit / metabolism
Leprosy / genetics*
Leprosy / immunology
Leprosy / metabolism
Male
MicroRNAs / genetics
MicroRNAs / immunology
MicroRNAs / metabolism
Middle Aged
Mycobacterium leprae / genetics
Mycobacterium leprae / immunology
Mycobacterium leprae / metabolism
Promoter Regions, Genetic / genetics
Promoter Regions, Genetic / immunology
T-Lymphocytes, Regulatory / immunology
T-Lymphocytes, Regulatory / metabolism
Th1 Cells / immunology
Th1 Cells / metabolism
Th2 Cells / immunology
Th2 Cells / metabolism
Transcription, Genetic / genetics*
Transcription, Genetic / immunology
Young Adult

Substances

CTLA-4 Antigen
FOXP3 protein, human
Forkhead Transcription Factors
IL2 protein, human
IL2RA protein, human
Interleukin-2
Interleukin-2 Receptor alpha Subunit
MicroRNAs
Histone Deacetylases