title: CD4+CD25+ T regs with acetylated FoxP3 are associated with immune suppression in human leprosy.
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.
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Kumar
authors.forename: Raza Ali
authors.initials: RA
authors.lastname: Naqvi
authors.forename: Riyasat
authors.initials: R
authors.lastname: Ali
authors.forename: Richa
authors.initials: R
authors.lastname: Rani
authors.forename: Neena
authors.initials: N
authors.lastname: Khanna
authors.forename: D N
authors.initials: DN
authors.lastname: Rao
mesh_terms: D000107:Acetylation; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000293:Adolescent; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology* / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D007918:Leprosy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D054875:Ubiquitination; D055815:Young Adult
chemical_list: C508504:6,7-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; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D007546:Isoquinolines; D050778:NFATC Transcription Factors; D011725:Pyridines; D011758:Pyrroles; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D016572:Cyclosporine; D017493:Leukocyte Common Antigens
keywords: Acetylated FoxP3; Leprosy; M. leprae; T regs; Tr1; Ubiquitination