Lymph-node (LN) stromal cell populations expand during the inflammation that accompanies T cell activation. Interleukin-17 (IL-17)-producing helper T cells (TH17 cells) promote inflammation through the induction of cytokines and chemokines in peripheral tissues. We demonstrate a critical requirement for IL-17 in the proliferation of LN and splenic stromal cells, particularly fibroblastic reticular cells (FRCs), during experimental autoimmune encephalomyelitis and colitis. Without signaling via the IL-17 receptor, activated FRCs underwent cell cycle arrest and apoptosis, accompanied by signs of nutrient stress in vivo. IL-17 signaling in FRCs was not required for the development of TH17 cells, but failed FRC proliferation impaired germinal center formation and antigen-specific antibody production. Induction of the transcriptional co-activator IκBζ via IL-17 signaling mediated increased glucose uptake and expression of the gene Cpt1a, encoding CPT1A, a rate-limiting enzyme of mitochondrial fatty acid oxidation. Hence, IL-17 produced by locally differentiating TH17 cells is an important driver of the activation of inflamed LN stromal cells, through metabolic reprogramming required to support proliferation and survival.

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Data availability

The RNA-Seq datasets generated for Figs. 6 and 7 are available at GEO accession code GSE124649. All other data used to generate figures for the study are available upon request by the corresponding author.

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Funding for this study was provided by the following grants: NIH Nos. AI110822 and AI128991 (to M.J.M.), No. T32-AI089443 (to I.R.), No. DK104680 (to P.S.B.), Nos. DE022550, DE023815 and AI107825 (to S.L.G.), and No. DP2AI136598 (to G.M.D); and R.K. Mellon Institute for Pediatric Research No. AACR SU2C-AACR-IRG-04-16 (to T.W.H). This research was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided. We thank V. Kuchroo (Harvard University) for Il23r–/– mice, P. Kolattukudy (University of Central Florida) for Zc3h12a+/– mice, J. Kolls (Tulane University) for Il17rafl/fl mice (now available at JAX labs) and L. D’Cruz for critical reading of the manuscript.

Author information


  1. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    • Saikat Majumder
    • , Nilesh Amatya
    • , Shankar Revu
    • , Chetan V. Jawale
    • , Dongwen Wu
    • , Saran Kupul
    • , Fang Du
    • , Itay Raphael
    • , Sarah L. Gaffen
    • , Partha S. Biswas
    •  & Mandy J. McGeachy
  2. Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA

    • Natalie Rittenhouse
    • , Amrita Bhattacharjee
    • , Timothy W. Hand
    •  & Amanda C. Poholek
  3. Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA

    • Ashley Menk
    •  & Greg M. Delgoffe
  4. Immune Activation Section, NIAID, National Institutes of Health, Bethesda, MD, USA

    • Ulrich Siebenlist


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S.M. and M.J.M. conceptualized and designed the study, performed analysis and wrote the manuscript. S.M., N.A., S.R., C.V.J., P.S.B., D.W. and A.M. performed experiments. N.R., I.R., N.A., A.C.P. and S.K. performed or assisted with analysis. F.D., A.B., U.S., T.W.H., G.M.D., S.L.G., P.S.B. and M.J.M. assisted with methodology, resources and analysis of experiments. T.W.H., A.P., P.S.B. and M.J.M. reviewed and edited the manuscript.

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The authors declare no competing interests.

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Correspondence to Mandy J. McGeachy.

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