title: IL-27 and IL-21 are associated with T cell IL-10 responses in human visceral leishmaniasis.
abstract: IL-10 is believed to underlie many of the immunologic defects in human visceral leishmaniasis (VL). We have identified CD4(+)CD25(-)Foxp3(-) T cells as the major source of IL-10 in the VL spleen. IL-27, a member of the IL-6/IL-12 cytokine family, has been shown to promote development of IL-10-producing T cells, in part by upregulating their production of autocrine IL-21. We investigated whether IL-27 and IL-21 are associated with human VL. IL-27 was elevated in VL plasma, and at pretreatment, spleen cells showed significantly elevated mRNA levels of both IL-27 subunits, IL-27p28 and EBI-3, as well as IL-21, compared with posttreatment biopsies. CD14(+) spleen cells were the main source of IL-27 mRNA, whereas CD3(+) T cells were the main source of IL-21. IL-27 mRNA could be strongly upregulated in normal donor macrophages with IFN-γ and IL-1β, conditions consistent with those in the VL spleen. Last, a whole-blood assay revealed that most VL patients could produce Ag-specific IFN-γ and IL-10 and that the IL-10 could be augmented with recombinant human IL-21. Thus, proinflammatory cytokines acting on macrophages in the VL spleen have the potential to upregulate IL-27, which in turn can induce IL-21 to expand IL-10-producing T cells as a mechanism of feedback control.
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Nasim Akhtar
authors.initials: NA
authors.lastname: Ansari
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.forename: Shalini
authors.initials: S
authors.lastname: Gautam
authors.forename: Susanne
authors.initials: S
authors.lastname: Nylén
authors.forename: Om Prakash
authors.initials: OP
authors.lastname: Singh
authors.forename: Shyam
authors.initials: S
authors.lastname: Sundar
authors.forename: David
authors.initials: D
authors.lastname: Sacks
mesh_terms: D000328:Adult; D025461:Feedback, Physiological / Q000502:physiology; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000097:blood / Q000502:physiology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000097:blood; D007378:Interleukins / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D007898:Leishmaniasis, Visceral / Q000097:blood / Q000276:immunology* / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000276:immunology; D055815:Young Adult; D000098546:Interleukin-21
chemical_list: C508609:IL10 protein, human; D020381:Interleukin-17; D007378:Interleukins; C464565:MYDGF protein, human; D012333:RNA, Messenger; D016753:Interleukin-10; D000098546:Interleukin-21