title: Highly heterogeneous, activated, and short-lived regulatory T cells during chronic filarial infection.
abstract: The mechanisms underlying the increase in the numbers of regulatory T (Treg) cells in chronic infection settings remain unclear. Here we have delineated the phenotype and transcriptional profiles of Treg cells from 18 filarial-infected (Fil(+) ) and 19 filarial-uninfected (Fil(-) ) subjects. We found that the frequencies of Foxp3(+) Treg cells expressing CTLA-4, GITR, LAG-3, and IL-10 were significantly higher in Fil(+) subjects compared with that in Fil(-) subjects. Foxp3-expressing Treg-cell populations in Fil(+) subjects were also more heterogeneous and had higher expression of IL-10, CCL-4, IL-29, CTLA-4, and TGF-β than Fil(-) subjects, each of these cytokines having been implicated in immune suppression. Moreover, Foxp3-expressing Treg cells from Fil(+) subjects had markedly upregulated expression of activation-induced apoptotic genes with concomitant downregulation of those involved in cell survival. To determine whether the expression of apoptotic genes was due to Treg-cell activation, we found that the expression of CTLA-4, CDk8, RAD50, TNFRSF1A, FOXO3, and RHOA were significantly upregulated in stimulated cells compared with unstimulated cells. Taken together, our results suggest that in patent filarial infection, the expanded Treg-cell populations are heterogeneous, short-lived, activated, and express higher levels of molecules known to modulate immune responsiveness, suggesting that filarial infection is associated with high Treg-cell turnover.
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Metenou
authors.forename: Yaya I
authors.initials: YI
authors.lastname: Coulibaly
authors.forename: Daniel
authors.initials: D
authors.lastname: Sturdevant
authors.forename: Housseini
authors.initials: H
authors.lastname: Dolo
authors.forename: Abdallah A
authors.initials: AA
authors.lastname: Diallo
authors.forename: Lamine
authors.initials: L
authors.lastname: Soumaoro
authors.forename: Michel E
authors.initials: ME
authors.lastname: Coulibaly
authors.forename: Kishore
authors.initials: K
authors.lastname: Kanakabandi
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Porcella
authors.forename: Amy D
authors.initials: AD
authors.lastname: Klion
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Nutman
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D017209:Apoptosis; D060908:CTLA-4 Antigen / Q000032:analysis; D002908:Chronic Disease; D005260:Female; D005368:Filariasis / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000032:analysis; D006801:Humans; D016753:Interleukin-10 / Q000032:analysis; D008213:Lymphocyte Activation; D008297:Male; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016753:Interleukin-10; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human
keywords: Chronic infection; Foxp3; Regulatory T (Treg) cells; Regulatory molecules
references.citation: J Immunol. 2011 Apr 15;186(8):4725-33
references.pmid: 21411732
references.citation: PLoS One. 2012;7(10):e44915
references.pmid: 23071503
references.citation: Proc Natl Acad Sci U S A. 2007 May 8;104(19):8029-34
references.pmid: 17483450
references.citation: Immunity. 1997 Jun;6(6):673-9
references.pmid: 9208840
references.citation: J Allergy Clin Immunol. 2008 May;121(5):1108-11
references.pmid: 18405958
references.citation: J Immunol. 2006 Mar 1;176(5):3248-56
references.pmid: 16493086
references.citation: Curr Opin Immunol. 2010 Oct;22(5):575-82
references.pmid: 20829012
references.citation: J Immunol. 2011 Aug 15;187(4):1684-91
references.pmid: 21746966
references.citation: Eur J Immunol. 2002 Mar;32(3):858-67
references.pmid: 11870630
references.citation: Parasitology. 2011 Jan;138(1):35-45
references.pmid: 20619070
references.citation: J Immunol. 2002 Jul 15;169(2):750-7
references.pmid: 12097377
references.citation: J Immunol. 2013 Mar 1;190(5):2001-8
references.pmid: 23359504
references.citation: J Immunol. 2010 May 1;184(9):5375-82
references.pmid: 20357251
references.citation: J Immunol. 2005 Apr 15;174(8):4924-33
references.pmid: 15814720
references.citation: Infect Immun. 2000 Nov;68(11):6402-10
references.pmid: 11035752
references.citation: Eur J Immunol. 2008 Nov;38(11):3101-13
references.pmid: 18924213
references.citation: Ann N Y Acad Sci. 2008 Dec;1150:234-8
references.pmid: 19120302
references.citation: Eur J Immunol. 2012 Mar;42(3):641-50
references.pmid: 22213332
references.citation: Proc Natl Acad Sci U S A. 2007 May 29;104(22):9469-74
references.pmid: 17517597
references.citation: Innate Immun. 2009 Dec;15(6):325-35
references.pmid: 19675119
references.citation: J Immunol. 2012 Jul 1;189(1):381-92
references.pmid: 22661091
references.citation: J Exp Med. 2010 Oct 25;207(11):2331-41
references.pmid: 20876311
references.citation: Endocrinology. 2009 Dec;150(12):5218-29
references.pmid: 19819943
references.citation: PLoS Negl Trop Dis. 2011 Aug;5(8):e1286
references.pmid: 21886851
references.citation: Infect Immun. 2009 Dec;77(12):5334-46
references.pmid: 19805535
references.citation: Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9649-54
references.pmid: 21606368
references.citation: PLoS Negl Trop Dis. 2013 Dec 12;7(12):e2586
references.pmid: 24349595
references.citation: Clin Immunol. 2012 Dec;145(3):209-23
references.pmid: 23110942
references.citation: Trans R Soc Trop Med Hyg. 2013 May;107(5):293-300
references.pmid: 23442572
references.citation: J Infect Dis. 1996 Mar;173(3):769-73
references.pmid: 8627051
references.citation: Eur J Immunol. 2001 Mar;31(3):792-801
references.pmid: 11241284
references.citation: Blood. 2011 Jul 28;118(4):984-91
references.pmid: 21652680
references.citation: J Exp Med. 2007 Apr 16;204(4):805-17
references.pmid: 17389235
references.citation: Immunology. 2011 Dec;134(4):434-47
references.pmid: 22044159
references.citation: Acta Trop. 2011 Dec;120(3):191-205
references.pmid: 21875568
references.citation: J Biochem. 2008 Mar;143(3):295-302
references.pmid: 18079163
references.citation: Immunol Cell Biol. 2008 Nov-Dec;86(8):650-8
references.pmid: 18794907
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5919-24
references.pmid: 20231436
references.citation: J Immunol. 2008 Nov 15;181(10):7147-56
references.pmid: 18981136
references.citation: Clin Immunol. 2011 Dec;141(3):244-52
references.pmid: 21945485
references.citation: J Immunol. 2012 Sep 1;189(5):2118-30
references.pmid: 22821963
references.citation: Gastroenterology. 2011 Jul;141(1):249-58, 258.e1-2
references.pmid: 21569774
references.citation: Am J Trop Med Hyg. 2008 Jun;78(6):924-8
references.pmid: 18541771
references.citation: Exp Parasitol. 1996 Nov;84(2):282-90
references.pmid: 8932778
references.citation: Parasite Immunol. 1995 Aug;17(8):385-92
references.pmid: 7501419
references.citation: J Infect Dis. 2008 Jan 1;197(1):94-101
references.pmid: 18171291
references.citation: J Virol. 2011 Jul;85(13):6702-13
references.pmid: 21525347
references.citation: Parasite Immunol. 2005 Oct-Nov;27(10-11):417-29
references.pmid: 16179035
references.citation: J Exp Med. 2007 Feb 19;204(2):285-97
references.pmid: 17283207
references.citation: Immunity. 2011 Jul 22;35(1):13-22
references.pmid: 21777796
references.citation: Nat Immunol. 2013 Apr;14(4):307-8
references.pmid: 23507634
references.citation: Nat Med. 2011 Jun;17(6):673-5
references.pmid: 21540856
references.citation: Biochim Biophys Acta. 2010 Aug;1806(1):42-9
references.pmid: 20122997
references.citation: Eur J Immunol. 1998 Oct;28(10):3161-71
references.pmid: 9808185
references.citation: Reumatismo. 2012 Dec 11;64(5):293-8
references.pmid: 23256104
references.citation: Infect Immun. 2005 Jun;73(6):3394-401
references.pmid: 15908366
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 21;102(25):9014-9
references.pmid: 15956184
references.citation: PLoS One. 2009 Aug 19;4(8):e6695
references.pmid: 19690611
references.citation: Cytokine Growth Factor Rev. 2010 Aug;21(4):237-51
references.pmid: 20655797
references.citation: Eur J Immunol. 2012 Sep;42(9):2431-40
references.pmid: 22685028
references.citation: Emerg Infect Dis. 2007 Apr;13(4):608-10
references.pmid: 17553278
references.citation: J Immunol. 2008 Feb 15;180(4):2367-75
references.pmid: 18250446
references.citation: J Immunol. 2001 Sep 15;167(6):3207-15
references.pmid: 11544307
references.citation: J Trop Pediatr. 2014 Jun;60(3):245-8
references.pmid: 24343822
references.citation: Am J Respir Cell Mol Biol. 2008 May;38(5):591-9
references.pmid: 18096868
references.citation: Blood. 1994 Dec 15;84(12):4008-27
references.pmid: 7994020
references.citation: Am J Pathol. 2010 May;176(5):2177-87
references.pmid: 20382703
references.citation: Ann N Y Acad Sci. 2012 Dec;1274:68-76
references.pmid: 23252899
references.citation: MMWR Morb Mortal Wkly Rep. 2011 Jul 29;60(29):989-91
references.pmid: 21796097
references.citation: Microbes Infect. 2001 Sep;3(11):947-54
references.pmid: 11564443
references.citation: J Immunol. 2009 Jul 15;183(2):916-24
references.pmid: 19561105
references.citation: PLoS Negl Trop Dis. 2009;3(4):e410
references.pmid: 19352421
references.citation: J Infect Dis. 1996 Jan;173(1):269-72
references.pmid: 8537675
references.citation: Vaccine. 2008 Jul 23;26(31):3897-902
references.pmid: 18554755
references.citation: Immunol Rev. 2001 Aug;182:68-79
references.pmid: 11722624
references.citation: Parasitol Res. 2009 Sep;105(3):731-41
references.pmid: 19452170
references.citation: PLoS Negl Trop Dis. 2012;6(5):e1655
references.pmid: 22666510
references.citation: Blood. 2006 Jun 1;107(11):4417-23
references.pmid: 16478884
references.citation: J Infect Dis. 1988 Nov;158(5):1034-7
references.pmid: 2460565
references.citation: Wkly Epidemiol Rec. 2007 Oct 19;82(42):361-80
references.pmid: 17948605
references.citation: Microbes Infect. 2002 Nov;4(13):1291-300
references.pmid: 12443893
references.citation: Lung Cancer. 2012 Dec;78(3):185-92
references.pmid: 23021208