Skip to main content

SFB 1192

Project A5

Th17 cell plasticity in renal autoimmune disease

In the past, CD4+ T cell subsets have been viewed as terminally differentiated lineages with limited flexibility. However, Th17 cells can have a high degree of plasticity and convert for example into pro-inflammatory Th1 cells or anti-inflammatory Tr1 cells. Interestingly, Th17 cells in experimental GN display limited spontaneous plasticity, as we have shown in this project. We furthermore introduced anti-CD3 injection as a tool to induce a regulatory phenotype in Th17 cells and trans-differentiation of Th17 cells into immunosuppressive IL-10-expressing Tr1 cells (Tr1exTh17 cells). Thus, targeting Th17 cell plasticity could be envisaged as a therapy in GN. However, the underlying mechanisms regulating stability and plasticity in Th17 cells are unclear to a large extent. To get insights into these mechanisms, we compared transcriptional profiles of stable renal and instable intestinal Th17 cells as well as of Tr1exTh17 cells obtained by bulk RNA-sequencing and single cell RNA-sequencing (scRNA-seq). On the basis of these data we aim now at uncovering the molecular basis for renal Th17 stability and at finding therapeutic targets for the modulation of the Th17 immune response. We will specifically address the following points: 1. Mechanisms of Th17 cell stability and plasticity (validation of specific candidates as identified in the first funding period (i.e. TCF-7, TOX, IL-27- receptor; in vivo CROP-seq for high-throughput screening of further potential candidates); 2. Environmental shaping of the Th17 immune response in the kidney compared to the intestine (interactome of Th17 cells and tissue cells; impact of human intestinal bacteria from ANCA-GN patients on Th17 cell plasticity and disease outcome in experimental models using patientspecific gnotobiotic mice). 3. Identification of developmental trajectories of human renal T cells by using the TCR as an endogenous barcode (TCR-sequencing and transcriptome analysis at the single cell level). Our long-term goal is to identify mechanisms shifting Th17 cells towards a regulatory phenotype that could be used as a therapeutic strategy in patients with glomerulonephritis in the future.

Selected Publications:

  • Targeting T cell plasticity in kidney and gut inflammation by pooled single-cell CRISPR screening.

    Enk LUB, Hellmig M, Riecken K, Kilian C, Datlinger P, Jauch-Speer SL, Neben T, Sultana Z, Sivayoganathan V, Borchers A, Paust HJ, Zhao Y, Asada N, Liu S, Agalioti T, Pelczar P, Wiech T, Bock C, Huber TB, Huber S, Bonn S, Gagliani N, Fehse B, Panzer U, Krebs CF.  Sci Immunol. 2024 Jun

  • Immune profiling-based targeting of pathogenic T cells with ustekinumab in ANCA-associated glomerulonephritis.

    Engesser J, Khatri R, Schaub DP, Zhao Y, Paust HJ, Sultana Z, Asada N, Riedel JH, Sivayoganathan V, Peters A, Kaffke A, Jauch-Speer SL, Goldbeck-Strieder T, Puelles VG, Wenzel UO, Steinmetz OM, Hoxha E, Turner JE, Mittrücker HW, Wiech T, Huber TB, Bonn S, Krebs CF#, Panzer U.  Nat Commun. 2024 Sep

  • Clonal expansion and activation of tissue-resident memory-like Th17 cells expressing GM-CSF in the lungs of severe COVID-19 patients.

    Zhao Y, Kilian C, Turner JE, Bosurgi L, Roedl K, Bartsch P, Gnirck AC, Cortesi F, Schultheiss C, Hellmig M, Enk LUB, Hausmann F, Borchers A, Wong MN, Paust HJ, Siracusa F, Scheibel N, Herrmann M, Rosati E, Bacher P, Kylies D, Jarczak D, Lutgehetmann M, Pfefferle S, Steurer S, Zur-Wiesch JS, Puelles VG, Sperhake JP, Addo MM, Lohse AW, Binder M, Huber S, Huber TB, Kluge S, Bonn S, Panzer U, Gagliani N, Krebs CF. Sci Immunol. 2021 Feb

  • Pathogen-induced tissue-resident memory T(H)17 (T(RM)17) cells amplify autoimmune kidney disease.

    Krebs CF, Reimers D, Zhao Y, Paust HJ, Bartsch P, Nunez S, Rosemblatt MV, Hellmig M, Kilian C, Borchers A, Enk LUB, Zinke M, Becker M, Schmid J, Klinge S, Wong MN, Puelles VG, Schmidt C, Bertram T, Stumpf N, Hoxha E, Meyer-Schwesinger C, Lindenmeyer MT, Cohen CD, Rink M, Kurts C, Franzenburg S, Koch-Nolte F, Turner JE, Riedel JH, Huber S, Gagliani N, Huber TB, Wiech T, Rohde H, Bono MR, Bonn S, Panzer U, Mittrucker HW. Sci Immunol. 2020 Aug

  • Autoimmune Renal Disease Is Exacerbated by S1P-Receptor-1-Dependent Intestinal Th17 Cell Migration to the Kidney.

    Krebs CF, Paust HJ, Krohn S, Koyro T, Brix SR, Riedel JH, Bartsch P, Wiech T, Meyer-Schwesinger C, Huang J, Fischer N, Busch P, Mittrucker HW, Steinhoff U, Stockinger B, Perez LG, Wenzel UO, Janneck M, Steinmetz OM, Gagliani N, Stahl RAK, Huber S, Turner JE, Panzer U. Immunity. 2016 Nov