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 7

Treatment of EAE WT mice with IL-4 results in disease amelioration, CD4+ T cell migration to the gut, increased RALDH activity in dendritic cells, and upregulation of gut-homing markers on CD4+ T cells.

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Treatment of EAE WT mice with IL-4 results in disease amelioration, CD4+...
(A) EAE scores in WT mice treated with recombinant IL-4 (WT IL-4) versus saline-treated controls (WT). P ≤ 0.05 after day 12; n = 5 (mean ± SEM). (B) Absolute numbers of CD4+ T cells from dLNs and mLNs of the indicated groups on day 12 after EAE induction. *P ≤ 0.05; n = 4 (mean ± SEM). (C) FACS analysis of frequencies (left) and average frequencies (right) of CD4+ T cells in the CNS, SILP, and Peyer patches in the indicated groups on day 18 following EAE induction. *P ≤ 0.05, n = 4 (mean ± SEM). (D) FACS analysis of CCR9 levels on CD4+ T cells (left) and average frequencies of CCR9+CD4+ T cells (right) from dLNs and mLNs of the indicated groups. *P ≤ 0.05, n = 4 (mean ± SEM). (E) FACS analysis of α4β7 levels on CD4+ T cells (left) and average frequencies of α4β7+CD4+ T cells (right) from dLNs and mLNs of indicated groups. *P ≤ 0.05, n = 4 (mean ± SEM). (F) ALDH activity in dendritic cells from dLNs and mLNs of EAE mice treated with IL-4 or saline. Right panel shows average frequencies of ALDH-producing cells. *P ≤ 0.05, n = 4 (mean ± SEM). The gray shaded areas represent DEAB-treated samples. Two-tailed Student’s t test was applied to determine significance in all cases.