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 6

Retrieval and adoptive transfer of fibrosis-memory is dependent on T cell–derived IL-3.

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Retrieval and adoptive transfer of fibrosis-memory is dependent on T cel...
(A) RUUO of the right kidney (day 0–6, first insult) followed by UUO of the left kidney (day 16–22, second insult). Treatment with anti–IL-3 (n = 20) or isotype control antibody (n = 18; 4 pooled experiments, same controls as in Figure 2A) from day 15–21. Analysis of the left UUO kidneys on day 22. (B) WT or IL-3–KO mice underwent RUUO of the right kidney (day 0–6, first insult) or remained naive (Ø). All mice then underwent UUO of the left kidney (day 16–22). Analysis of the left UUO kidneys on day 22. One experiment with n = 7, WT RUUO+UUO; 7, IL-3-KO RUUO+UUO; 6, WT UUO; and 7, IL-3-KO UUO. (C) Splenic CD62L–CD4+ or renal CD4+ T cells were purified from the spleens or fibrotic kidneys of RUUO+UUO donor mice (RUUO from day –18 to –12 and UUO of the same kidney from day –7 to 0). Medium, 4 × 106 splenic CD62L–CD4+ or 67,000 renal CD4+ T cells were injected into recipients on day 0. UUO in all recipients on day 0. Treatment with anti–IL-3 or an isotype control antibody (Ø) from day 0–6. Analysis of the recipient’s UUO kidneys on day 7. Single experiment with n = 8, no cell transfer; 5, no cell transfer and anti–IL-3; 7, transfer of CD62L- from spleen; 7, transfer of CD62L- from spleen and anti–IL-3; 3, transfer of CD4+ from UUO kidney; and 3, transfer of CD4+ from UUO kidney and anti–IL-3. (D) Splenic CD62L–CD4+ or renal CD4+ T cells were purified from the spleens or fibrotic kidneys of WT or IL-3–deficient (IL-3 KO) RUUO+UUO mice, as in C. Medium (Ø), 4 × 106 splenic CD62L–CD4+ or 116,000 renal CD4+ T cells were injected on day 0. UUO in all recipients on day 0. Analysis of the recipient’s UUO kidneys on day 7. Single experiment with n = 7, no cell transfer; 8, CD62L+ from spleen of WT; 7, CD62L+ from spleen of IL-3 KO; 5, CD62L+ from UUO-kidney of WT; and 8, CD62L+ from UUO-kidney of IL-3 KO. Data are represented as mean ± SEM. Unpaired 2-sided t test. *P < 0.05; **P < 0.01; ***P < 0.001.