Diverting T helper cell trafficking through increased plasticity attenuates autoimmune encephalomyelitis
Danielle Califano, … , David M. Jones, Dorina Avram
Danielle Califano, … , David M. Jones, Dorina Avram
Published December 9, 2013
Citation Information: J Clin Invest. 2014;124(1):174-187. https://doi.org/10.1172/JCI70103.
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Research Article Immunology

Diverting T helper cell trafficking through increased plasticity attenuates autoimmune encephalomyelitis

Abstract

Naive T helper cells differentiate into functionally distinct effector subsets that drive specialized immune responses. Recent studies indicate that some of the effector subsets have plasticity. Here, we used an EAE model and found that Th17 cells deficient in the transcription factor BCL11B upregulated the Th2-associated proteins GATA3 and IL-4 without decreasing RAR-related orphan receptor γ (RORγt), IL-17, and GM-CSF levels. Surprisingly, abnormal IL-4 production affected Th17 cell trafficking, diverting migration from the draining lymph nodes/CNS route to the mesenteric lymph nodes/gut route, which ameliorated EAE without overt colitis. T helper cell rerouting in EAE was dependent on IL-4, which enhanced retinoic acid (RA) production by dendritic cells, which further induced expression of gut-homing receptors CCR9 and α4β7 on Bcl11b-deficient CD4+ T cells. Furthermore, IL-4 treatment or Th2 immunization of wild-type mice with EAE caused no alteration in Th17 cytokines or RORγt, but diverted T helper cell trafficking to the gut, which improved EAE outcome without overt colitis. Our data demonstrate that Th17 cells are permissive to Th2 gene expression without affecting Th17 gene expression. This Th17 plasticity has an impact on trafficking, which is a critical component of the immune response and may represent a possible avenue for treating multiple sclerosis.

Authors

Danielle Califano, Keith J. Sweeney, Hung Le, Jeffrey VanValkenburgh, Eric Yager, William O’Connor Jr., Jeffrey S. Kennedy, David M. Jones, Dorina Avram

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Figure 2

Bcl11bF/F/dLck-iCre mice show delayed onset of EAE with reduced severity caused by diminished CD4+ T cell infiltration in the CNS, without alteration in CNS trafficking receptors.

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Bcl11bF/F/dLck-iCre mice show delayed onset of EAE with reduced severit...
(A) EAE disease scores of Bcl11bF/F/dLck-iCre (black) and WT (gray) mice following EAE induction, as described in Methods. P ≤ 0.05 starting on day 12, n = 11 (mean ± SEM). Data are representative of 4 independent experiments. (B) H&E staining of spinal cord (top) and brain (bottom) of Bcl11bF/F/dLck-iCre and WT mice 18 days after EAE induction. Scale bars: 200 μm. Red arrows indicate mononuclear infiltrates. Blue arrows indicate tissue damage. (C) FACS analysis of CD4+ T cells in the CNS of Bcl11bF/F/dLck-iCre and WT mice on day 18 following EAE induction. (D) Frequencies of IL-17– and GM-CSF–producing CD4+ T cells in CNS on day 18 after immunization. (E and F) Same as in C and D, in EAE Bcl11bF/F/dLck-iCre/2D2 and 2D2 mice. (G) Absolute numbers of CD4+ T cells (left) and CD4+IL-17+GM-CSF+ (right) in the CNS of EAE Bcl11bF/F/dLck-iCre (black) and WT (white) mice. *P ≤ 0.05, n = 6 (mean ± SEM). (H) FACS analysis of CCR6, itgβ1, CD11a, and CD18 levels on CD4+ T cells from dLNs of the indicated EAE mice on day 12 following EAE induction. In all plots, gray shaded area indicates negative control. Two-tailed Student’s t test was applied to determine significance.