title: miR-182 and miR-10a are key regulators of Treg specialisation and stability during Schistosome and Leishmania-associated inflammation.
abstract: A diverse suite of effector immune responses provide protection against various pathogens. However, the array of effector responses must be immunologically regulated to limit pathogen- and immune-associated damage. CD4(+)Foxp3(+) regulatory T cells (Treg) calibrate immune responses; however, how Treg cells adapt to control different effector responses is unclear. To investigate the molecular mechanism of Treg diversity we used whole genome expression profiling and next generation small RNA sequencing of Treg cells isolated from type-1 or type-2 inflamed tissue following Leishmania major or Schistosoma mansoni infection, respectively. In-silico analyses identified two miRNA "regulatory hubs" miR-10a and miR-182 as critical miRNAs in Th1- or Th2-associated Treg cells, respectively. Functionally and mechanistically, in-vitro and in-vivo systems identified that an IL-12/IFNγ axis regulated miR-10a and its putative transcription factor, Creb. Importantly, reduced miR-10a in Th1-associated Treg cells was critical for Treg function and controlled a suite of genes preventing IFNγ production. In contrast, IL-4 regulated miR-182 and cMaf in Th2-associed Treg cells, which mitigated IL-2 secretion, in part through repression of IL2-promoting genes. Together, this study indicates that CD4(+)Foxp3(+) cells can be shaped by local environmental factors, which orchestrate distinct miRNA pathways preserving Treg stability and suppressor function.
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Samir
authors.initials: S
authors.lastname: Kelada
authors.forename: Praveen
authors.initials: P
authors.lastname: Sethupathy
authors.forename: Isobel S
authors.initials: IS
authors.lastname: Okoye
authors.forename: Eleni
authors.initials: E
authors.lastname: Kistasis
authors.forename: Stephanie
authors.initials: S
authors.lastname: Czieso
authors.forename: Sandra D
authors.initials: SD
authors.lastname: White
authors.forename: David
authors.initials: D
authors.lastname: Chou
authors.forename: Craig
authors.initials: C
authors.lastname: Martens
authors.forename: Stacy M
authors.initials: SM
authors.lastname: Ricklefs
authors.forename: Kimmo
authors.initials: K
authors.lastname: Virtaneva
authors.forename: Dan E
authors.initials: DE
authors.lastname: Sturdevant
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Porcella
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Belkaid
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wynn
authors.forename: Mark S
authors.initials: MS
authors.lastname: Wilson
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D012550:Schistosoma mansoni / Q000276:immunology*; D012555:Schistosomiasis mansoni / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology
chemical_list: D016207:Cytokines; C569259:MIRN10 microRNA, mouse; D035683:MicroRNAs; C540524:Mirn182 microRNA, mouse