Maintaining self-tolerance in a steady state and regulating ongoing immune responses are critical for preserving immune homeostasis and the prevention of autoimmunity. Therefore, multiple cell populations with regulatory capacities have developed, including both lymphocytes and myeloid cell types. The essential and dominant suppressive nature of Foxp3+ Tregs is illustrated by the fact that mice and humans lacking those cells develop fatal autoimmune disease but over the last years, many studies have identified other suppressive populations including different myeloid cell types (e.g. MDSCs, regDCs, M2 macrophages). These cells are particularly prevalent in solid tumours and have been shown to promote tumour growth. Furthermore, some of these cells were also found to have immunosuppressive functions in other conditions such as inflammation, infection and autoimmunity.
We have recently shown that autoreactive B cells, producing auto-antibodies against tissue specific autoantigens against the kidney, are directly suppressed by Treg cells via PD-1/PD-L1 interaction. Suppression resulted in reduced antibody production by B cells, expansion of autoreactive B cells as well as induction of apoptosis of the autoreactive B cells. Additionally we have identified a kidney-residing population of MDSCs that express IFNgRβ during "crystal-induced" kidney inflammation and these cells have potent T-cell suppressive activity. Thus, similar to reports on Tregs, our current observations suggest that unique MDSC populations exist in various organs and possess unique functional features.
1. Identification of key molecules that induce PD-1 upregulation and PD1/PD-L1 mediated apotosis in autoreactive B cells
Following our recently identified mechanism of PD-1/PD-L1 interaction during the elimination of tissue specific autoreactive B cells by Tregs, we are currently analysing the sequence of molecular signals that leads to the increasing expression of PD-1 on autoreactive B cells. Identifying these molecular checkpoints would be important to develop a better treatment of autoantibody-dependent disorders or for improving vaccinations.
2. Role and function of myeloid-derived suppressor cells in kidney inflammation
CD11b+Gr1+ myeloid derived suppressor cells (MDSC) are known to be very potent suppressors of T cell immunity and based on expression of Ly6G or Ly6C can be further discriminated into granulocytic MDSC and monocytic MDSC. Recently we identified that the suppressive function within the MDSC population in the kidney was exclusive to IFNγRβ expressing cells. Our continuing research is to identify suppressive mechanisms and the cell populations that are regulated during kidney inflammation by MDSCs.
3. Molecular regulation of suppressive lymphocytes and myeloid immune cells in non-lymphoid tissues
In this project, the aim is to analyse the molecular regulation of immune suppression in non-lymphoid tissues. Specifically, we focus on how tissue-derived cytokines such as IL-33 and transcriptional regulators, such as IRF and BATF family members, known to be expressed by myeloid cell populations as well in lymphocytes, impact on the development and function of suppressive myeloid cells including DCs and MDSCs. In particular, we examine how these molecular regulators control the transcriptional and metabolic profiles of DCs and MDSCs within the inflamed tissue.
4. Interplay of innate lymphoid cells and regulatory T cells in inflammasome dependent nephritis
Inflammasome-induced nephritis is mainly triggered by activated dendritic cells and macrophages via the production of pro-inflammatory cytokines such as IL-1b, TNF, IL-6 and IL-18. ILCs seem to promote an inflamed environment by enhancing the inflammatory process and by interacting with CD4+ T helper cells. In this project we investigate the interplay of regulatory T cells and ILCs in NLRP3-inflammasome-induced kidney inflammation. Here, we will specifically focus on the role of NLRP3-inflammasome-induced cytokines on the activation and plasticity of the renal ILC populations.
- Innate Lymphoid Cells (SPP 1937)