Abstract
Lymphatic filariasis (LF) remains a major health problem with severe economic repercussions in endemic communities of Sub-saharan Africa, South-East Asia and South America. The rodent-specific nematode Litomosoides sigmodontis (Ls) is used to study the immunomodulatory potential of filariae and research has elucidated pathways involving regulatory T cells (Tregs), IL-10 producing cells and alternatively activated macrophages (AAMs) and that CD4+ T cells play a paramount role during infection. Myeloid-derived suppressor cells (MDSCs) have been identified and characterised in man in cancer and other pathologies. The hallmark of MDSC populations is the suppression of T and B cell responses using various mechanisms, which are mostly specific to the pathology or setting. However, until now, it remains unclear whether they play a role in filarial-specific responses. We report here that monocytic MDSCs (Mo-MDSCs, CD11b+Ly6C+Ly6G-) and polymorphonuclear MDSCs (PMN-MDSCs, CD11b+Ly6Cint/loLy6G+) expanded in the thoracic cavity (TC, the site of infection) and correlated positively with filarial life-stages in Ls-infected BALB/c mice. In vitro, only infection-derived Mo-MDSCs showed a suppressive nature by preventing IL-13 and IFN-γ secretion from filarial-specific CD4+ T cells upon co-culture with soluble worm extract. This suppression was not mediated by IL-10, IL-6 or TNF-α, and did not require cell-contact, nitric oxide (NO), IL-4/IL-5 signalling pathways or CCR2. Interestingly, neutralizing TGF-β significantly rescued IFN-γ but not IL-13 production by filarial-specific CD4+ T cells. In comparison to naive cells, PCR array data showed an overall down-regulation of inflammatory pathways in both infection-derived Mo-MDSCs and PMN-MDSCs. In conclusion, these primary data sets show activity and expansion of MDSCs during Ls infection adding this regulatory cell type to the complex milieu of host responses during chronic helminth infections.
Highlights
65 million people are infected with Lymphatic filariasis (LF) worldwide [1]
Very few Mo-Myeloid-derived suppressor cells (MDSCs) or PMN-MDSCs were present in the thoracic cavity (TC) of naive mice (Figure 1B) whereas substantial numbers of these cells comprised the cellular milieu in Litomosoides sigmodontis (Ls)-infected mice 72 days p.i. (Figure 1B)
Correlation analysis of worm burden or MF counts with MDSC numbers indicated that levels of both Mo-MDSCs and PMN-MDSCs positively correlated with worm burden (Figure 1D) and MF in the TC (Figure 1E)
Summary
65 million people are infected with LF worldwide [1]. To understand mechanisms underlying immunity to filarial infections in man, such as Wuchereria bancrofti which elicits lymphatic filariasis (LF) [2, 3], researchers employ the Litomosoides sigmodontis (L. sigmodontis, Ls) rodent model since it reflects several aspects of LF infection. The development of adult worms from larval stages in the host provokes different immune reactions and encompasses both innate (neutrophils, eosinophils and basophils) and adaptive responses (T and B cells). Two subsets of MDSCs, the monocytic MDSCs (Mo-MDSCs, CD11b+Ly6C+Ly6G-) and the polymorphonuclear MDSCs (PMN-MDSCs, CD11b+Ly6Cint/loLy6G+) have been identified in patients and murine models of disease These include cancer, systemic inflammation and sepsis, autoimmune diseases as well as bacterial, viral and parasitic infections [18,19,20,21,22,23,24,25,26]. An adoptive transfer of these cells induced higher parasite burden indicating that these cells promoted chronic infection [28] This current work explored the role of Mo- and PMN-MDSCs over the course of Ls infection in BALB/c mice. Both MDSC subsets were present in the thoracic cavity (TC), the site of infection and levels
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