The relevance of myeloid-derived suppressor cells during Litomosoides sigmodontis infection

Abstract

68 million people are infected with lymphatic filariasis (LF) in Sub-Saharan Africa, South-East Asia and South America, causing a major health problem with economic repercussions among the infected populations. This disease is caused by three species of filarial nematode parasites such as <em>Wuchereria bancrofti, Brugia malayi </em>and<em> Brugia timori</em>. In infected patients, only 50% become patent (release microfilariae, MF) and this is well represented in the laboratory BALB/c mice when naturally infected with <em>Litomosoides sigmodontis</em> (Ls). Infection with Ls has been shown to induce regulatory cell populations including Tregs, IL-10 producing cells and alternative activated macrophages (AAMs) and more importantly, CD4⁺ T cells have been found to play a paramount role during the infection. In fact, previous observations have revealed the impairment of Ls filarial stages induced by these cells. Recently, Myeloid-Derived Suppressor Cells (MDSCs) have been characterized in cancer and other pathologies including bacterial, viral and parasitic infections. There are two subsets of MDSCs: monocytic MDSCs (Mo-MDSCs) and granulocytic or polymorphonuclear MDSCs (PMN-MDSCs) both identified in man and murine models. The hallmark of either MDSC populations is the suppression of T and B cell responses using various mechanisms which are mostly specific to the pathology or setting. For instance, there is evidence that MDSCs can suppress and accumulate through receptors such as the Interleukin 4 receptor-alpha (IL-4α), Tumor necrosis receptor 2 (TNFR2) and C-C motif chemokine receptor 2 (CCR2) or they use soluble factors such as nitric oxide (NO), reactive oxygen species (ROS) and transforming growth factor-beta (TGF-β), to function. MDSCs have been shown to interfere in host-pathogen interactions and various research studies consider those cells as a new therapeutic target to control resistance to diseases such as cancer. However, it remains unclear whether they play a role in helminth infections, especially if they could affect filarial development or filarial-specific responses and would be able to serve as tool to overcome filariasis. Thus, the current work verified the hypothesis of a possible role of MDSC populations during Ls infection in BALB/c mice by means of parasitological analyses, flow cytometry and a specifically designed <em>in vitro</em> cell culture assay to measure their suppressive activities on CD4⁺ T cells. The results revealed that populations of MDSC subsets expanded in the thoracic cavity (TC), the site of infection, of infected mice whereas only very few MDSCs were found in naive mice. This expansion correlated positively with worm burden. Interestingly, although numbers of PMN-MDSCs in the TC were higher than amounts of Mo-MDSCs, the latter showed high suppressive abilities on the production of IL-13 and IFNγ by Ls-specific CD4⁺ T cells in a cell-contact independent manner. Further analyses demonstrated that Mo-MDSCs used distinct functional mechanisms such as nitric oxide (NO) and TGF-β to impair the production of IL-13 and IFN-γ, respectively. Surprisingly, comparisons of PCR array data on isolated MDSC populations from infected and naive mice displayed an overall shut-down of inflammatory pathways in both infection-derived MDSC subsets and therefore supporting filarial establishment. In conclusion, the involvement of MDSCs during Ls infection offered a favorable milieu for parasite development, impairing host immunity, and therefore targeting MDSCs may provide a therapeutic tool to fight filariasis.