title: Induction of IL-10 and TGFβ from CD4+CD25+FoxP3+ T Cells Correlates with Parasite Load in Indian Kala-azar Patients Infected with Leishmania donovani.
abstract: BACKGROUND
  Visceral leishmaniasis (VL) is distinguished by a complex interplay of immune response and parasite multiplication inside host cells. However, the direct association between different immunological correlates and parasite numbers remains largely unknown.
  
  
  RESULTS
  We examined the plasma levels of different disease promoting/protective as well as Th17 cytokines and found IL-10, TGFβ and IL-17 to be significantly correlated with parasite load in VL patients (r = 0.52, 0.53 and 0.51 for IL-10, TGFβ and IL-17, respectively). We then extended our investigation to a more antigen-specific response and found leishmanial antigen stimulated levels of both IL-10 and TGFβ to be significantly associated with parasite load (r = 0.71 and 0.72 for IL-10 and TGFβ respectively). In addition to cytokines we also looked for different cellular subtypes that could contribute to cytokine secretion and parasite persistence. Our observations manifested an association between different Treg cell markers and disease progression as absolute numbers of CD4+CD25+ (r = 0.55), CD4+CD25hi (r = 0.61) as well as percentages of CD4+CD25+FoxP3+ T cells (r = 0.68) all correlated with parasite load. Encouraged by these results, we investigated a link between these immunological components and interestingly found both CD4+CD25+ and CD4+CD25+FoxP3+ Treg cells to secrete significantly (p<0.05) higher amounts of not only IL-10 but also TGFβ in comparison to corresponding CD25- T cells.
  
  
  CONCLUSIONS
  Our findings shed some light on source(s) of TGFβ and suggest an association between these disease promoting cytokines and Treg cells with parasite load during active disease. Moreover, the direct evidence of CD4+CD25+FoxP3+ Treg cells as a source of IL-10 and TGFβ during active VL could open new avenues for immunotherapy towards cure of this potentially fatal disease.
authors.affiliation: Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Kolkata, West Bengal, India.
authors.forename: Pradyot
authors.initials: P
authors.lastname: Bhattacharya
authors.affiliation: Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Kolkata, West Bengal, India.
authors.forename: Smriti
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Kolkata, West Bengal, India.
authors.forename: Sarfaraz Ahmad
authors.initials: SA
authors.lastname: Ejazi
authors.affiliation: Department of Tropical Medicine, School of Tropical Medicine, Kolkata, West Bengal, India.
authors.forename: Mehebubar
authors.initials: M
authors.lastname: Rahaman
authors.affiliation: Department of Clinical Medicine, Rajendra Memorial Research Institute of Medical Sciences, Patna, Bihar, India.
authors.forename: Krishna
authors.initials: K
authors.lastname: Pandey
authors.affiliation: Department of Clinical Medicine, Rajendra Memorial Research Institute of Medical Sciences, Patna, Bihar, India.
authors.forename: Vidya Nand
authors.initials: VN
authors.lastname: Ravi Das
authors.affiliation: Department of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences, Patna, Bihar, India.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Das
authors.affiliation: Department of Tropical Medicine, School of Tropical Medicine, Kolkata, West Bengal, India.
authors.forename: Rama Prosad
authors.initials: RP
authors.lastname: Goswami
authors.affiliation: Department of Tropical Medicine, School of Tropical Medicine, Kolkata, West Bengal, India.
authors.forename: Bibhuti
authors.initials: B
authors.lastname: Saha
authors.affiliation: Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Kolkata, West Bengal, India.
authors.forename: Nahid
authors.initials: N
authors.lastname: Ali
mesh_terms: D000328:Adult; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D016022:Case-Control Studies; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D006801:Humans; D007194:India / Q000208:ethnology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D007893:Leishmania donovani / Q000276:immunology / Q000502:physiology*; D007898:Leishmaniasis, Visceral / Q000208:ethnology / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D008297:Male; D059208:Parasite Load; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology*; D055815:Young Adult
chemical_list: D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; D016753:Interleukin-10
references.citation: J Infect Dis. 1998 Mar;177(3):815-8
references.pmid: 9498473
references.citation: Indian J Med Res. 2006 Mar;123(3):245-66
references.pmid: 16778308
references.citation: Am J Trop Med Hyg. 1997 May;56(5):522-5
references.pmid: 9180602
references.citation: Infect Immun. 1997 Jun;65(6):2371-7
references.pmid: 9169776
references.citation: PLoS Negl Trop Dis. 2011 Jul;5(7):e1198
references.pmid: 21765960
references.citation: PLoS One. 2012;7(5):e37393
references.pmid: 22693573
references.citation: Eur J Clin Microbiol Infect Dis. 2014 Apr;33(4):639-49
references.pmid: 24173820
references.citation: Parasite Immunol. 2010 Jul;32(7):479-83
references.pmid: 20591118
references.citation: PLoS Negl Trop Dis. 2010;4(7):e764
references.pmid: 20668544
references.citation: J Immunol. 2007 Oct 15;179(8):5592-603
references.pmid: 17911647
references.citation: Invest Ophthalmol Vis Sci. 2013;54(10):6926-33
references.pmid: 24065812
references.citation: J Clin Invest. 1993 Jul;92(1):324-9
references.pmid: 8326000
references.citation: PLoS Pathog. 2012;8(7):e1002827
references.pmid: 22911108
references.citation: Am J Trop Med Hyg. 1995 May;52(5):438-42
references.pmid: 7771611
references.citation: Ann Trop Med Parasitol. 2009 Dec;103(8):671-7
references.pmid: 20030991
references.citation: Infect Immun. 2005 Sep;73(9):5908-14
references.pmid: 16113310
references.citation: Semin Immunol. 2004 Apr;16(2):89-98
references.pmid: 15036232
references.citation: Front Immunol. 2012 Jun 04;3:129
references.pmid: 22675324
references.citation: Infect Genet Evol. 2011 Jul;11(5):912-6
references.pmid: 21376140
references.citation: J Immunol. 1992 Mar 15;148(6):1792-6
references.pmid: 1541819
references.citation: Trans R Soc Trop Med Hyg. 2001 Jan-Feb;95(1):85-8
references.pmid: 11280075
references.citation: Immunol Res. 2010 Jul;47(1-3):14-24
references.pmid: 20087685
references.citation: J Immunol. 2008 Mar 15;180(6):4090-7
references.pmid: 18322219
references.citation: Front Immunol. 2012 Apr 17;3:80
references.pmid: 22566961
references.citation: J Immunol. 2011 Apr 1;186(7):3977-85
references.pmid: 21357266
references.citation: Nat Protoc. 2006;1(3):1507-16
references.pmid: 17406442
references.citation: PLoS One. 2012;7(2):e31551
references.pmid: 22347492
references.citation: Clin Immunol. 2006 Jun;119(3):339-45
references.pmid: 16540374
references.citation: Eur J Immunol. 2010 Oct;40(10):2830-6
references.pmid: 20812234
references.citation: Trans R Soc Trop Med Hyg. 1961 Nov;55:550-5
references.pmid: 14469435
references.citation: J Immunol. 2008 May 1;180(9):6139-48
references.pmid: 18424735
references.citation: J Infect Dis. 1992 Mar;165(3):535-40
references.pmid: 1347057
references.citation: J Clin Invest. 2009 Aug;119(8):2379-87
references.pmid: 19620772
references.citation: Clin Vaccine Immunol. 2012 Jun;19(6):961-6
references.pmid: 22539471
references.citation: Trends Immunol. 2007 Sep;28(9):378-84
references.pmid: 17689290
references.citation: PLoS One. 2012;7(5):e35671
references.pmid: 22693548
references.citation: Biomed Res Int. 2014;2014:361058
references.pmid: 24895569
references.citation: BMC Infect Dis. 2005;5:113
references.pmid: 16364177
references.citation: PLoS Pathog. 2009 Aug;5(8):e1000543
references.pmid: 19680449
references.citation: J Clin Invest. 1993 Apr;91(4):1644-8
references.pmid: 8097208
references.citation: Parasitol Res. 2009 Apr;104(5):1129-36
references.pmid: 19057926
references.citation: Rev Inst Med Trop Sao Paulo. 2009 Sep-Oct;51(5):241-6
references.pmid: 19893975
references.citation: J Exp Med. 2007 Apr 16;204(4):805-17
references.pmid: 17389235
references.citation: Braz J Infect Dis. 2009 Feb;13(1):44-6
references.pmid: 19578629
references.citation: J Infect Dis. 2006 May 1;193(9):1313-22
references.pmid: 16586370
references.citation: J Biol Chem. 1951 Nov;193(1):265-75
references.pmid: 14907713
references.citation: Nature. 2002 Dec 5;420(6915):502-7
references.pmid: 12466842
references.citation: J Immunol. 1995 May 1;154(9):4623-9
references.pmid: 7722314
references.citation: J Immunol. 2011 Mar 15;186(6):3373-82
references.pmid: 21307296
references.citation: PLoS Pathog. 2013 Mar;9(3):e1003243
references.pmid: 23555256
references.citation: PLoS Negl Trop Dis. 2011;5(5):e1171
references.pmid: 21655313
references.citation: PLoS One. 2010;5(4):e10107
references.pmid: 20404924
references.citation: Infect Immun. 1993 Mar;61(3):1069-73
references.pmid: 8432588
references.citation: Front Immunol. 2012 Aug 14;3:251
references.pmid: 22912637
references.citation: Clin Diagn Lab Immunol. 1997 May;4(3):309-13
references.pmid: 9144369
references.citation: BMC Immunol. 2014;15:16
references.pmid: 24886212
references.citation: J Antimicrob Chemother. 2011 Aug;66(8):1751-5
references.pmid: 21609983
references.citation: Hum Immunol. 2014 Oct;75(10):1026-33
references.pmid: 25167770
references.citation: Trop Med Int Health. 2004 Dec;9(12):1305-11
references.pmid: 15598262