Helminth protection against autoimmune diabetes in nonobese diabetic mice is independent of a type 2 immune shift and requires TGF-β

Marc P. Hübner, Yinghui Shi, Marina N. Torrero, Ellen Mueller, David Larson, Kateryna Soloviova, Fabian Gondorf, Achim Hoerauf, Kristin E. Killoran, J. Thomas Stocker, Stephen J. Davies, Kristin V. Tarbell, Edward Mitre*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

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.

Original languageEnglish
Pages (from-to)559-568
Number of pages10
JournalJournal of Immunology
Volume188
Issue number2
DOIs
StatePublished - 15 Jan 2012

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