Fibrosis-memory is mediated by IL-3–producing T cells and drives progression of fibrosis
Simone Buchtler, Antje Frühauf, Sophia Neumayer, Kathrin Schmidbauer, Yvonne Talke, Frederike Winter-Köhler, Saidou Balam, Karin Landgraf, Claudia Gebhard, Michael Rehli, Florian Volker Schlieckau, Maria Beck, Florian Günther, Martin Fleck, Kerstin Renner, Matthias Mack
Simone Buchtler, Antje Frühauf, Sophia Neumayer, Kathrin Schmidbauer, Yvonne Talke, Frederike Winter-Köhler, Saidou Balam, Karin Landgraf, Claudia Gebhard, Michael Rehli, Florian Volker Schlieckau, Maria Beck, Florian Günther, Martin Fleck, Kerstin Renner, Matthias Mack
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Research Article Immunology Nephrology

Fibrosis-memory is mediated by IL-3–producing T cells and drives progression of fibrosis

Abstract

Repetitive injuries are an important trigger of progressive fibrosis. To study if repetitive injuries induce an accelerated profibrotic process, also called “fibrosis-memory,” we established an experimental system with two consecutive, clearly separated insults in a model of renal fibrosis with reversible and irreversible unilateral ureteral obstruction. We found that a preceding fibrotic event of one kidney markedly enhanced subsequent development of fibrosis in the contralateral kidney. Aggravation of fibrosis during the second insult was dependent on memory CD4+ T cells. T cell depletion abrogated the fibrosis-memory effect, while adoptive transfer of memory T cells from fibrotic mice enhanced fibrosis in the recipients. Moreover, IL-3 production by memory CD4+ T cells was essential for aggravation of fibrosis in memory situations. In patients with systemic sclerosis, IL-3 expression by T cells was markedly increased, especially after a long disease duration accompanied by involvement of internal organs. In summary, our data identify IL-3–mediated fibrosis-memory as an important driver of progressive fibrosis.

Authors

Simone Buchtler, Antje Frühauf, Sophia Neumayer, Kathrin Schmidbauer, Yvonne Talke, Frederike Winter-Köhler, Saidou Balam, Karin Landgraf, Claudia Gebhard, Michael Rehli, Florian Volker Schlieckau, Maria Beck, Florian Günther, Martin Fleck, Kerstin Renner, Matthias Mack

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Figure 3

Fibrosis-memory can be adoptively transferred by splenic and renal CD4+ T cells.

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Fibrosis-memory can be adoptively transferred by splenic and renal CD4+ ...
(A and B) CD4+ and CD8+ T cells were purified on day 0 from the spleens of naive donor mice (no OP) or donor mice after RUUO of the right kidney from day –18 to –12 and UUO of the same kidney from day –7 to 0 (RUUO+UUO). Where indicated, RPMI-1640 medium (Ø) or 5 × 106 CD4+ T cells or CD8+ T cells were adoptively transferred into recipients on day 0 and UUO was performed on all recipients on day 0. (A) Quantification of collagen-1 (Col1), overall fibrosis (fibrotic area), and col1a1 mRNA expression in the recipient’s UUO kidneys on day 7. Two pooled experiments with n = 11, no cell transfer; 13, CD4+ T cells from naïve mice; 13, CD8+ T cells from naïve mice; 14, CD4+ T cells from mice after RUUO+UUO; and 13, CD8+ T cells from mice after RUUO+UUO. (B) Representative images of collagen-1 immunofluorescence and Trichrome staining. (C and D) CD4+ T cells were purified on day 0 from the spleens or fibrotic kidneys of donor mice, with renal fibrosis induced as described above (RUUO+UUO). Where indicated, medium or 130,000 CD4+ T cells were adoptively transferred into recipients on day 0 and UUO was performed on all recipients on day 0. (C) Analysis of the recipient’s UUO kidneys on day 7. Two pooled experiments with n = 14, no cell transfer; 8, CD4+ T cells from the spleen; and 12, CD4+ T cells from the UUO kidney. (D) Representative images of collagen-1 immunofluorescence and Trichrome staining. Scale bars: 100 μm. Data are represented as mean ± SEM. One-way ANOVA with multiple comparisons (A and C). *P < 0.05; **P < 0.01; ***P < 0.001.