Transcriptional profiling, cytokine requirement and function of myeloid-derived suppressor cells (MDSC) in the Mesocestoides corti Type 2 infection model

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Myeloid-derived suppressor cells (MDSC) play important roles in the control of type 1 immune responses against tumors, viruses or bacteria. Factors leading to the generation of MDSC in these diseases are increasingly well understood. In contrast, reports on the occurrence and suppression mechanisms of MDSC in worm or parasite infections (type 2 immunity) are much less studied. While crucial differences for the polarization of macrophages, dendritic cells and T helper cells between type 1 and 2 infections are well documented, it is unclear whether such a dichotomy also occurs for MDSC. Since factors like GM-CSF, IFN-g and iNOS, hallmarks of type 1 immunity, do not occur or only marginally occur in type 2 immunity, other cytokines and effectors must lead to the generation and activation of MDSC in type 2 immunity. Our preliminary data indicate that IL-3 and Arg1 both typical characteristics of type 2 immunity may represent such factors. Our preliminary data show the successful generation of MDSC by IL-3 in vitro and the enriched frequencies of Arg1 producing MDSC in the type 2 immunity cestode model of Mesocestoides corti infection. Here we aim to employ state-of the art mouse models, cytokine blocking antibodies or drugs, as well as single cells RNA-sequencing to characterize MDSC in this type 2 infection. We will employ the M. corti infection model to investigate 1) the functional role of granulocytic and monocytic MDSC subsets during different stages of infection for suppression of T cells and dendritic cells, 2) the role of IL-3 as compared with GM-CSF for MDSC generation and 3) Arg1 as a suppressor mechanism compared with iNOS. The results will allow not only reveal phenotypical, transcriptional and functional differences between MDSC subsets in type 1 versus type 2 infection, but we will also test whether interference with MDSC generation or function represents a therapeutic option in type 2 infections. Overall, MDSC in type 2 infections are insufficiently investigated and are the subject of our project proposal. Since these diseases often involve chronic diseases with severe burdens and also fatal consequences, a better understanding of MDSC induction in type 2 infections and the identification of new avenues for immune intervention is of considerable clinical importance.