A pro-inflammatory role of TH1 and TH17 responses in glomerulonephritis has been well established by us and others. Much less, however, is known about the mechanisms downregulating nephritogenic TH1 and TH17 immunity. In this respect, T cells with anti-inflammatory properties were shown to be of central importance. Among these are Foxp3+ regulatory T cells (Treg) which have initially been thought to be a homogenous population. It has recently become clear, however, that a high degree of diversity exists. In this respect, the new concept of lineage specific Tregs has been proposed. Treg1 cells are tailor made to suppress pro-inflammatory TH1 responses while Treg17 cells are specialized to dampen TH17 responses. Interestingly, both Treg1 and Treg17 cells develop under the influence of transcription factors shared with their pro-inflammatory counterparts, namely T-bet (TH1/Treg1) and Stat3 (TH17/Treg17).

The biology and function of Treg1 and Treg17 cells remains largely unknown to date and their role in renal disease is only just emerging. In addition to Treg1 and Treg17 cells, further pathways regulating TH1 and TH17 responses exist. Among these is the IL-10 signaling cascade which has been postulated to down regulate TH17 responses via multiple mechanisms. These include direct anti-inflammatory effects on TH17 cells as well as indirect effects via modulating regulatory T cell functions. Furthermore, the multi-functional cytokine IL-6 has emerged as potent regulator of TH1 and TH17 responses.

 Given the increasing use of IL-6 directed therapies for treatment of an expanding array of immune mediated diseases, a detailed understanding of IL-6 biology is of great clinical importance. While IL-6 has been shown to be implicated in development of pro-inflammatory TH17 responses, recent data by us and others suggest additional anti-inflammatory functions. Critical roles for Treg homeostasis as well as IL-6 dependent induction of regulatory T cell type1 (Tr1) and CD8+Foxp3+ regulatory T cells have been postulated. The in vivo relevance of these novel and intriguing IL-6 functions for inflammatory diseases, including glomerulonephritis, remains widely unknown.

This project therefore aims to address the following issues:

1. Development and function of Treg1 cells in models of acute and chronic GN.
2. Characterization of the role of IL-10 receptor signaling for regulating TH17 responses in acute and chronic GN.
3. Analysis of Treg1 and Treg17 cells in patients with crescentic glomerulonephritis.
4. Definition of T cell subtype specific roles of IL-6 signaling in acute GN with special focus on Treg function as well as Tr1 and CD8+Foxp3+ cell generation.

Our data support a new paradigm. Regulatory T cells can specialize into Treg1- and Treg17-cells for optimized down regulation of nephritogenic Th1- and Th17-responses. An important mechanism used, is the directional migration into the same areas as their pathogenic counterparts. This is facilitated by shared expression of chemokine receptors CXCR3 on Th1 and Treg1, as well as CCR6 on Th17 and Treg17 cells respectively. Furthermore a positive feedback loop via IL-10 secretion from Tregs which enhances Treg functions seems to be a mechanism for potent down regulation of Th17 Immunity.