Defining immunosuppressive profiles of MDSCs in chronic helminth infections

• Applicant: Dr. Laura Elizabeth Layland-Heni
• Subject Area: Immunology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 418102129

Although there is increasing awareness that myeloid-derived suppressor cells (MDSCs) become active following exposure to pathogens, little is known about their behaviour in infectious settings, especially helminthic diseases. Adult Litomosoides sigmodontis (Ls) nematodes are confined to the thoracic cavity (TC) in mice allowing precise studies of cell populations that infiltrate this area and moreover have direct contact with the helminth and infected host tissues. Current investigations from our group have revealed that populations of monocytic (Mo)-MDSC (CD11b+Ly6C+Ly6G-) and polymorphonuclear (PMN)-MDSCs (CD11b+Ly6Cint/loLy6G+) accumulate into the TC during Ls infection. Moreover, by establishing a MDSC:CD4+ T cell suppression assay, it can be observed that isolated Mo-MDSCs from the TC suppress Ls-specific CD4+ T cell responses following stimulation with adult worm antigen. The suppression of released cytokines (IL-13, IFN-γ) by CD4+ T cells was independent of the IL-4Ralpha, cell contact, CCR2, IL-10, IL-6 or TNF-alpha but did require nitric oxide release (in the case of IL-13) and TGF-beta (in the case of IFN-gamma). Interestingly PMN-MDSCs did not suppress T cell responses in vitro showing the complexity of Ls-induced immune regulation and highlight that distinct MDSCs populations induce different functional mechanisms. The available funding from the Next Generation Sequencing (NGS) Platform will expand our knowledge on the gene expression profiles of MDSCs that develop during filarial nematode infections providing a basis for further in-depth analysis. These pre-clinical studies will be then compared to gene expression profiles of isolated MDSC populations from individuals infected with filariae that parasitize man and will reveal potential overlapping immunosuppressive features in MDSCs across filarial infections. The combination of in vivo, in vitro, cellular and genetic profiling in pre-clinical and clinical settings will provide an extensive data set and a platform to reveal strategies employed by the MDSCs to suppress these filarial-specific T cell responses. To fulfil these objectives a substantial contribution from the NGS platform is essential and analysis will be performed in collaboration with the available Core Unit for Bioinformatics Data Analysis (CUBA).

• DFG Programme: Research Grants