The role of novel Treg subtypes in glomerulonephritis
A key role for CD4+ T cells as mediators of inflammatory diseases, including glomerulonephritis (GN), has been firmly established. In particular, effector T cells of the T-helper 1 (Th1) and Thelper 17 (Th17) lineages were shown to be highly nephritogenic. On the other hand, regulatory T cells (Treg) have been identified as potent counter regulators of overshooting immune responses and protect from renal tissue injury. Pioneering studies have thus begun to evaluate Treg based therapies for immune mediated diseases. Interestingly, however, it has become clear in the recent past, that Tregs are by no means a uniform population. Rather, highly specialized subtypes of Tregs exist, which are tailor made for the control of a particular type of immune response. Treg1 cells can potently target Th1 and Treg17 cells down regulate Th17 immunity. In addition, a unique Treg subset has been discovered by us and others, which surprisingly expresses the Th17 master transcription factor RORγt and can produce the cytokine IL-17A. These RORγt+ Tregs have been shown to be effector Tregs with enhanced immunosuppressive capacity and potently protect from renal tissue injury. In line with their IL- 17A secretion, however, this unusual Treg population seems to have additional proinflammatory potential. Given their bi-functional nature, we proposed the operational name ´biTregs´. How and under which conditions biTregs exert their pro- and anti-inflammatory functions remains largely unknown to date. In summary, it becomes increasingly evident, that many aspects of the complex Treg biology have not yet been understood. We thus aim to address the following aspects: 1) Characterize the function of endogenous biTregs and identify their mechanisms of action. 2) Analyse the composition of Treg subsets in the blood of patients with Lupus and ANCA associated nephritis. 3) Study the cell type specific role of the chemokine CCL20, which we have in the past identified as a potential effector molecule of biTregs. 4) Evaluate effects of IL-2 receptor (IL-2R) stimulation with a novel mutated human IL-2 protein (´mutein´) on Treg expansion, subset composition and therapeutic potential for GN. Taken together, our studies aim to help advance our understanding of Treg biology and function. The final goal is to establish Treg based therapies for the treatment of GN.
The CCR6/CCL20 axis expands RORγt+ Tregs to protect from glomerulonephritis.
Georg R Herrnstadt, Christoph B Niehus, Torben Ramcke , Julia Hagenstein, Laura-Isabell Ehnold, Anna Nosko, Matthias T Warkotsch, Frederic C Feindt, Simon Melderis, Hans-Joachim Paust, Varshi Sivayoganathan, Saskia-Larissa Jauch-Speer, Milagros N Wong, Daniela Indenbirken, Christian F Krebs, Tobias B Huber, Ulf Panzer, Victor G Puelles, Malte A Kluger, Oliver M Steinmetz.Kidney Int. 2023 Mar
The Amphiregulin/EGFR axis protects from lupus nephritis via downregulation of pathogenic CD4+ T helper cell responses.
Simon Melderis, Matthias T Warkotsch, Julien Dang, Julia Hagenstein, Laura-Isabell Ehnold, Georg R Herrnstadt, Christoph B Niehus, Frederic C Feindt, Dominik Kylies, Victor G Puelles, Carmen Berasain, Matias A Avila, Katrin Neumann, Gisa Tiegs, Tobias B Huber, Pierre-Louis Tharaux, Oliver M Steinmetz.J Autoimmun 2022 May
Amphiregulin Aggravates Glomerulonephritis via Recruitment and Activation of Myeloid Cells.
Melderis S, Hagenstein J, Warkotsch MT, Dang J, Herrnstadt GR, Niehus CB, Neumann K, Panzer U, Berasain C, Avila MA, Tharaux PL, Tiegs G, Steinmetz OM.J Am Soc Nephrol. 2020 Sep
A Novel Role for IL-6 Receptor Classic Signaling: Induction of ROR γ t+Foxp3+ Tregs with Enhanced Suppressive Capacity.
Julia Hagenstein, Simon Melderis, Anna Nosko, Matthias T Warkotsch, Johannes V Richter, Torben Ramcke, Georg R Herrnstadt, Jürgen Scheller, Isabell Yan, Hans-Willi Mittrücker, Malte A Kluger, Oliver M Steinmetz.J Am Soc Nephrol. 2019 Aug
IL-10 Receptor Signaling Empowers Regulatory T Cells to Control Th17 Responses and Protect from GN.
Diefenhardt P, Nosko A, Kluger MA, Richter JV, Wegscheid C, Kobayashi Y, Tiegs G, Huber S, Flavell RA, Stahl RAK, Steinmetz OM.J Am Soc Nephrol. 2018 Jul
RORγt expression in Tregs promotes systemic lupus erythematosus via IL-17 secretion, alteration of Treg phenotype and suppression of Th2 responses.
Kluger MA, Nosko A, Ramcke T, Goerke B, Meyer MC, Wegscheid C, Luig M, Tiegs G, Stahl RA, Steinmetz OM.Clin Exp Immunol. 2017 Apr
T-Bet Enhances Regulatory T Cell Fitness and Directs Control of Th1 Responses in Crescentic GN.
Nosko A, Kluger MA, Diefenhardt P, Melderis S, Wegscheid C, Tiegs G, Stahl RA, Panzer U, Steinmetz OMJ Am Soc Nephrol. 2017 Jan
Treg17 cells are programmed by Stat3 to suppress Th17 responses in systemic lupus.
Kluger MA, Melderis S, Nosko A, Goerke B, Luig M, Meyer MC, Turner JE, Meyer-Schwesinger C, Wegscheid C, Tiegs G, Stahl RAK, Panzer U, Steinmetz OM.Kidney Int. 2016 Jan
RORγt+Foxp3+ cells are an independent bifunctional regulatory T cell lineage and mediate crescentic GN.
Kluger MA, Meyer MC, Nosko A, Goerke B, Luig M, Wegscheid C, Tiegs G, Stahl RA, Panzer U, Steinmetz OM.J Am Soc Nephrol. 2016 Feb
Stat3 programs Th17-specific regulatory T cells to control GN.
Kluger MA, Luig M, Wegscheid C, Goerke B, Paust HJ, Brix SR, Yan I, Mittrücker HW, Hagl B, Renner ED, Tiegs G, Wiech T, Stahl RAK, Panzer U, Steinmetz OM.J Am Soc Nephrol. 2014 Jun