Biology subjects

Paust, H.-J.

Publications and source records attributed to Paust, H.-J..

4 recordsLinked to original sources

bioRxiv2024

The integrated stress response/eIF2α pathway controls cytokine production in tissue-resident memory CD4+ T cells

Tissue-resident memory T (Trm) cells are a specialized T cell population that resides in tissues and can play both a protective and pathogenic role. The mechanism that enables Trm cells to provide a rapid protective response while restricting their function in homeostasis remains unclear. Here, we show that human and mouse CD4+ Trm cells exist in a poised state, characterized by storage of proinflammatory type-1 and type-3 cytokine mRNAs without protein production. In steady-state conditions, cytokine mRNA translation in Trm cells is suppressed by the integrated stress response (ISR)/eIF2 pathway, whereas Trm-cell activation under inflammatory conditions results in eIF2 dephosphorylation, leading to derepression and rapid translation of the cytokine mRNAs stored in stress granules. Pharmacological inhibition of eIF2 dephosphorylation resulted in reduced cytokine production from Trm cells, and ameliorated autoimmune kidney disease in mice. Consistent with these results, the ISR pathway in Trm cells was downregulated in patients with immune-mediated diseases of the kidney and the intestine. Our results identify ISR/eIF2-mediated control of cytokine mRNA translation as an underlying mechanism that restricts Trm cell activity in homeostasis but also promotes rapid response upon local infection or autoimmune reaction.

immunology↗

bioRxiv2023

Emergence and suppressive function of Tr1 cells in glomerulonephritis

T regulatory type 1 (Tr1) cells, which are defined by their regulatory function, lack of Foxp3, high expression of IL-10, CD49b, and LAG3, are known to be able to suppress Th1 and Th17 in the intestine. Th1 and Th17 cells are also the main drivers of crescentic glomerulonephritis, the most severe form of renal autoimmune disease. However, whether Tr1 cells emerge in renal inflammation and moreover, whether they exhibit regulatory function during glomerulonephritis has not been thoroughly investigated yet. To address these questions, we used a mouse model of experimental crescentic glomerulonephritis and double Foxp3mRFP IL-10eGFP reporter mice. We found that Foxp3neg IL-10-producing CD4+ T cells infiltrate the kidneys during glomerulonephritis progression. Using single-cell RNA- sequencing, we could show that these cells express the core transcriptional factors characteristic of Tr1 cells. In line with this, Tr1 cells showed a strong suppressive activity ex vivo and were protective in experimental crescentic glomerulonephritis in vivo. Finally, we could also identify Tr1 cells in the kidneys of patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis and define their transcriptional profile. Tr1 cells are currently used in several immune-mediated inflammatory diseases, e.g. as T- cell therapy. Thus, our study provides proof of concept for Tr1 cell-based therapies in experimental glomerulonephritis.

immunology↗

bioRxiv2022

Transcriptional and clonal characterization of cytotoxic CD8+ T cells in crescentic glomerulonephritis

Crescentic glomerulonephritis (cGN), most often caused by anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, is an aggressive form of immune-mediated kidney disease and represents an important cause of end-stage renal failure. Although it is known that T cells infiltrate the kidney in cGN, their precise role in autoimmune kidney disease remains to be fully elucidated. By performing single-cell analysis, we identified activated, clonally expanded CD8+ T cells with a cytotoxic gene expression profile in the kidneys of patients with ANCA-associated cGN. Using an experimental model of cGN, we demonstrated that clonally expanded murine CD8+ T cells highly expressed the cytotoxic molecule granzyme B. Moreover, lack of CD8+ T cells or granzyme B resulted in an ameliorated course of cGN. This was associated with reduced cleaved caspase-3 induction in renal tissue cells. Our data indicate that clonally expanded cytotoxic CD8+ T cells have a previously unrecognized pathogenic function in aggravating immune-mediated kidney disease.

immunology↗

bioRxiv2022

GM-CSF drives immune-mediated glomerular disease by licensing monocyte-derived cells to produce MMP12

Glomerulonephritis is a group of immune-mediated diseases that cause inflammation within the glomerulus and adjacent compartments of the kidney and is a major cause of end-stage renal disease. T cells are among the main drivers of glomerulonephritis. However, the T cell subsets, cytokine networks, and downstream effector mechanisms that lead to renal tissue injury are largely unknown, which has hindered the development of targeted therapies. Here we identify a population of GM-CSF-producing T cells that accumulates in the kidneys of patients with ANCA-associated glomerulonephritis, infiltrates the renal tissue in a mouse model of glomerulonephritis, and promotes tissue destruction and loss of renal function. Mechanistically, we show that GM-CSF producing T cells licence monocyte-derived cells to produce matrix metalloproteinase 12 (MMP12), which cleaves components of the glomerular basement membrane and exacerbates renal pathology. These findings provide a mechanistic rationale for the immunopathology of T cell-mediated diseases and identify the "GM-CSF - monocyte-derived cells - MMP12" pathway as a promising therapeutic target in treatment of glomerulonephritis.

immunology↗