IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis
Magdalena Huber, … , Thomas Kamradt, Michael Lohoff
Magdalena Huber, … , Thomas Kamradt, Michael Lohoff
Published December 10, 2012
Citation Information: J Clin Invest. 2013;123(1):247-260. https://doi.org/10.1172/JCI63681.
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Research Article Immunology

IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis

Abstract

IL-17–producing CD8+ T (Tc17) cells are detectible in multiple sclerosis (MS) lesions; however, their contribution to the disease is unknown. To identify functions of Tc17 cells, we induced EAE, a murine model of MS, in mice lacking IFN regulatory factor 4 (IRF4). IRF4-deficient mice failed to generate Tc17 and Th17 cells and were resistant to EAE. After adoptive transfer of WT CD8+ T cells and subsequent immunization for EAE induction in these mice, the CD8+ T cells developed a Tc17 phenotype in the periphery but could not infiltrate the CNS. Similarly, transfer of small numbers of WT CD4+ T cells alone did not evoke EAE, but when transferred together with CD8+ T cells, IL-17–producing CD4+ (Th17) T cells accumulated in the CNS and mice developed severe disease. Th17 accumulation and development of EAE required IL-17A production by CD8+ T cells, suggesting that Tc17 cells are required to promote CD4+ T cell–mediated induction of EAE. Accordingly, patients with early-stage MS harbored a greater number of Tc17 cells in the cerebrospinal fluid than in peripheral blood. Our results reveal that Tc17 cells contribute to the initiation of CNS autoimmunity in mice and humans by supporting Th17 cell pathogenicity.

Authors

Magdalena Huber, Sylvia Heink, Axel Pagenstecher, Katharina Reinhard, Josephine Ritter, Alexander Visekruna, Anna Guralnik, Nadine Bollig, Katharina Jeltsch, Christina Heinemann, Eva Wittmann, Thorsten Buch, Olivia Prazeres da Costa, Anne Brüstle, Dirk Brenner, Tak W. Mak, Hans-Willi Mittrücker, Björn Tackenberg, Thomas Kamradt, Michael Lohoff

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Figure 4

CD4+ T cells require CCR6 to cooperate with CD8+ T cells for infiltration into the CNS.

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CD4+ T cells require CCR6 to cooperate with CD8+ T cells for infiltratio...
(A) Mean clinical scores (± SEM) of MOG37–50-immunized Irf4–/– mice (n = 4) substituted with 107 WT CD45.2–CD8+ T plus 2.5 × 106 WT CD45.2+CD4+ T cells or Ccr6–/–CD45.2+CD4+ T cells. P values were calculated comparing the scores of Irf4–/– mice transferred with WT CD8+ T cells plus either WT CD4+ or Ccr6–/–CD4+ T cells. (B) qRT-PCR for Ccr6 mRNA in Irf4–/– (black) or WT (white) CD4+ T cells stimulated for 2 days as described. Data (± SD) of PCR duplicates. (C) Histology of spinal cords at day 26 after immunization: H&E staining (scale bar: 100 μm); immunochemically stained cells were detected as brown foci (scale bar: 50 μm). (A–C) The experiments were repeated twice with consistent results. **P < 0.005; ***P < 0.001.