Abstract
Leprosy is a chronic human disease that results from infection of Mycobacterium leprae. T reg cells have been shown to have important implications in various diseases. However, in leprosy, it is still unclear whether T regs can mediate immune suppression during progression of the disease. In the present study, we have proposed the putative mechanism leading to high proportion of T reg cells and investigated its significance in human leprosy. High levels of TGF-β followed by adaptation of FoxP3(+) naive and memory (CD4(+)CD45RA(+)/RO(+)) T cells were observed as the principal underlying factors leading to higher generation of T reg cells during disease progression. Furthermore, TGF-β was found to be associated with increased phosphorylation-mediated-nuclear-import of SMAD3 and NFAT towards BL/LL pole to facilitate FoxP3 expression in these cells, the same as justified after using nuclear inhibitors of SMAD3 (SIS3) and NFAT (cyclosporin A) in CD4(+)CD25(+) cells in the presence of TGF-β and IL-2. Interestingly, low ubiquitination of FoxP3 in T reg cells of BL/LL patients was revealed to be a major driving force in conferring stability to FoxP3 which in turn is linked to suppressive potential of T regs. The present study has also pinpointed the presence of CD4(+)CD25(+)IL-10(+) sub class of T regs (Tr1) in leprosy.
Keywords:
Acetylated FoxP3; Leprosy; M. leprae; T regs; Tr1; Ubiquitination.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Active Transport, Cell Nucleus / drug effects
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Adolescent
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Adult
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cyclosporine / pharmacology
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Female
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Forkhead Transcription Factors / immunology*
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Forkhead Transcription Factors / metabolism
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Humans
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Immunosuppressive Agents / pharmacology
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Interleukin-2 / immunology
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Interleukin-2 / metabolism
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Interleukin-2 / pharmacology
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Interleukin-2 Receptor alpha Subunit / immunology*
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Interleukin-2 Receptor alpha Subunit / metabolism
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Isoquinolines / pharmacology
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Leprosy / immunology*
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Leprosy / metabolism
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Leprosy / pathology
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Leukocyte Common Antigens / immunology
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Leukocyte Common Antigens / metabolism
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Male
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Middle Aged
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NFATC Transcription Factors / antagonists & inhibitors
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NFATC Transcription Factors / immunology
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NFATC Transcription Factors / metabolism
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Phosphorylation / drug effects
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Pyridines / pharmacology
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Pyrroles / pharmacology
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Smad3 Protein / antagonists & inhibitors
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Smad3 Protein / immunology
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Smad3 Protein / metabolism
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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Transforming Growth Factor beta / immunology
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / pharmacology
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Ubiquitination
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Young Adult
Substances
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6,7-dimethyl-2-(2E)-3-(1-methyl-2-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl-prop-2-enoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
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FOXP3 protein, human
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Forkhead Transcription Factors
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IL2RA protein, human
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Immunosuppressive Agents
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Interleukin-2
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Interleukin-2 Receptor alpha Subunit
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Isoquinolines
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NFATC Transcription Factors
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Pyridines
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Pyrroles
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Smad3 Protein
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Transforming Growth Factor beta
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Cyclosporine
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Leukocyte Common Antigens