title: Helminth protection against autoimmune diabetes in nonobese diabetic mice is independent of a type 2 immune shift and requires TGF-β.
abstract: Leading hypotheses to explain helminth-mediated protection against autoimmunity postulate that type 2 or regulatory immune responses induced by helminth infections in the host limit pathogenic Th1-driven autoimmune responses. We tested these hypotheses by investigating whether infection with the filarial nematode Litomosoides sigmodontis prevents diabetes onset in IL-4-deficient NOD mice and whether depletion or absence of regulatory T cells, IL-10, or TGF-β alters helminth-mediated protection. In contrast to IL-4-competent NOD mice, IL-4-deficient NOD mice failed to develop a type 2 shift in either cytokine or Ab production during L. sigmodontis infection. Despite the absence of a type 2 immune shift, infection of IL-4-deficient NOD mice with L. sigmodontis prevented diabetes onset in all mice studied. Infections in immunocompetent and IL-4-deficient NOD mice were accompanied by increases in CD4(+)CD25(+)Foxp3(+) regulatory T cell frequencies and numbers, respectively, and helminth infection increased the proliferation of CD4(+)Foxp3(+) cells. However, depletion of CD25(+) cells in NOD mice or Foxp3(+) T cells from splenocytes transferred into NOD.scid mice did not decrease helminth-mediated protection against diabetes onset. Continuous depletion of the anti-inflammatory cytokine TGF-β, but not blockade of IL-10 signaling, prevented the beneficial effect of helminth infection on diabetes. Changes in Th17 responses did not seem to play an important role in helminth-mediated protection against autoimmunity, because helminth infection was not associated with a decreased Th17 immune response. This study demonstrates that L. sigmodontis-mediated protection against diabetes in NOD mice is not dependent on the induction of a type 2 immune shift but does require TGF-β.
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Hübner
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Shi
authors.forename: Marina N
authors.initials: MN
authors.lastname: Torrero
authors.forename: Ellen
authors.initials: E
authors.lastname: Mueller
authors.forename: David
authors.initials: D
authors.lastname: Larson
authors.forename: Kateryna
authors.initials: K
authors.lastname: Soloviova
authors.forename: Fabian
authors.initials: F
authors.lastname: Gondorf
authors.forename: Achim
authors.initials: A
authors.lastname: Hoerauf
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Killoran
authors.forename: J Thomas
authors.initials: JT
authors.lastname: Stocker
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Davies
authors.forename: Kristin V
authors.initials: KV
authors.lastname: Tarbell
authors.forename: Edward
authors.initials: E
authors.lastname: Mitre
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000469:parasitology* / Q000517:prevention & control*; D005260:Female; D005368:Filariasis / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology*; D005370:Filarioidea / Q000276:immunology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000502:physiology; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000502:physiology
chemical_list: C556062:IL10 protein, mouse; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4