Immune regulatory mechanisms, not alteration in Th1/Th2 skewing, are responsible for helminth-mediated protection against type 1 diabetes in NOD mice. (116.3)

Abstract

Abstract Both Th2 immune responses and regulatory responses are increased during helminth infection and have the potential to be the mechanisms by which helminth infections protect against Th1-driven autoimmune diseases. We investigated these mechanisms by evaluating diabetes development in NOD mice infected with the filarial nematode Litomosoides sigmodontis in settings of depletion or absence of IL-4, regulatory T cells, IL-10, and TGFβ. Despite the absence of a Th2 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, increased proliferation of CD4+FoxP3+ cells, and increased production of TGFβ. Depletion of 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 TGFβ, but not blockade of IL-10 signaling, prevented the beneficial effect of helminth infection on diabetes. This study demonstrates that helminth-mediated protection against autoimmunity is not dependent on the induction of a Th2 shift but does require TGFβ. These findings suggest it may be possible to develop helminth-derived therapies for autoimmunity that induce protective regulatory responses without upregulating potentially harmful proallergic Th2 responses.