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 4

Fibrosis-memory leads to clonal expansion of CD4+ T cells in the kidney and increased IL-3 production.

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Fibrosis-memory leads to clonal expansion of CD4+ T cells in the kidney ...
(A and B) RUUO of the right kidney (day 0–6), followed by UUO of the left kidney (day 17–22). (A) Clonal diversity of UUO kidney and splenic CD4+ T cells on day 22. (B) TCR repertoire overlaps between UUO kidney and splenic CD4+ T cells. UMI counts represent individual TCR-β mRNAs. (C–I) RUUO of the right kidney (day 0–6) and UUO of the same kidney (day 11–18) (RUUO+UUO). Analysis on day 18. Naive mice (no OP) served as controls. (C) CD62L+ and CD62L– CD4+ T cells in the spleens of naive mice (n = 8), and in the spleens and fibrotic kidneys of RUUO+UUO mice (n = 6). (D) CD4+ T cells expressing IL-3, IL-2, GM-CSF, IFN-γ (n = 8 each), and IL-17 (n = 5) in the spleens and fibrotic kidneys of RUUO+UUO mice. (E) IL-3 mRNA expression of CD4+ T cells from the spleens of naive and RUUO+UUO mice (n = 8) and the fibrotic kidney of RUUO+UUO mice (n = 3). (F) IL-3 mRNA expression of CD62L+CD4+ T cells (n = 12) and CD62L–CD4+ T cells (n = 6) from the spleens of naive and RUUO+UUO mice. (G) IL-3 in the supernatant of anti-CD3–activated CD4+ T cells, CD62L+CD4+, and CD62L–CD4+ T cells from the spleens of RUUO+UUO mice (n = 3 per group). (H) IL-3 in the supernatant of anti-CD3–activated PBMCs from the blood of RUUO+UUO mice (n = 6) or naive mice (n = 7). (I) CFSE-labeled CD4+ T cells from the spleens of RUUO+UUO mice were injected into recipients 3 days after UUO operation (5 × 106 cells/mouse, n = 5). Two days later, CFSE+ T cells were quantified in relation to endogenous CFSE– CD4+ T cells in various organs. Data are represented as mean ± SEM. Unpaired 2-sided t test (A, D, F, and H) and 1-way ANOVA with multiple comparisons (C, E, G, and I). *P < 0.05; **P < 0.01; ***P < 0.001.