Patency of Litomosoides sigmodontis infection depends on Toll-like receptor 4 whereas Toll-like receptor 2 signalling influences filarial-specific CD4+ T-cell responses

Abstract

BALB/c mice develop a patent state [release of microfilariae (Mf), the transmission life-stage, into the periphery] when exposed to the rodent filariae Litomosoides sigmodontis. Interestingly, only a portion of the infected mice become patent, which reflects the situation in human individuals infected with Wuchereria bancrofti. Since those individuals had differing filarial-specific profiles, this study compared differences in immune responses between Mf+ and Mf- infected BALB/c mice. We demonstrate that cultures of total spleen or mediastinal lymph node cells from Mf+ mice produce significantly more interleukin-5 (IL-5) to filarial antigens but equal levels of IL-10 when compared with Mf- mice. However, isolated CD4+ T cells from Mf+ mice produced significantly higher amounts of all measured cytokines, including IL-10, when compared with CD4+ T-cell responses from Mf- mice. Since adaptive immune responses are influenced by triggering the innate immune system we further studied the immune profiles and parasitology in infected Toll-like receptor-2-deficient (TLR2-/-) and TLR4-/- BALB/c mice. Ninety-three per cent of L. sigmodontis-exposed TLR4-/- BALB/c mice became patent (Mf+) although worm numbers remained comparable to those in Mf+ wild-type controls. Lack of TLR2 had no influence on patency outcome or worm burden but infected Mf+ mice had significantly lower numbers of Foxp3+ regulatory T cells and dampened peripheral immune responses. Interestingly, in vitro culturing of CD4+ T cells from infected wild-type mice with granulocyte-macrophage colony-stimulating factor-derived TLR2-/- dendritic cells resulted in an overall diminished cytokine profile to filarial antigens. Hence, triggering TLR4 or TLR2 during chronic filarial infection has a significant impact on patency and efficient CD4+ T-cell responses, respectively.