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 6

IL-4 is essential for increased RALDH activity in dendritic cells, upregulation of gut-homing receptors, and CD4+ T cell rerouting and disease amelioration in EAE Bcl11bF/F/dLck-iCre mice.

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IL-4 is essential for increased RALDH activity in dendritic cells, upreg...
(A) EAE scores of the indicated groups, treated with IL-4NA or IgG. P ≤ 0.05 for Bcl11bF/F/dLck-iCre IL-4NA–treated versus IgG-treated, starting with day 12; n = 5 per group (mean ± SEM). (B) Absolute numbers of CD4+ T cells in the indicated groups on day 12 after EAE induction.*P ≤ 0.05; NS, P > 0.05, n = 6 (mean ± SEM). (C) Frequencies by FACS analysis (left) and average frequencies (right) of CD4+ T cells in the indicated tissues and groups on day 18 after induction. *P ≤ 0.05; NS, P > 0.05, n = 4 (mean ± SEM). (D and E) α4β7 integrin (D) and CCR9 (E) evaluated by FACS analysis on CD4+ T cells from dLNs and mLNs of the indicated groups on day 12 after EAE induction. (F) Flow cytometry analysis of ALDH activity in CD3–CD11c+CD103+ dendritic cells from mLNs and dLNs of the indicated groups on day 12 after EAE induction. (D–F) Lower panels show the average frequencies of the data in the panels above. *P ≤ 0.05; NS, P > 0.05; n = 4 (mean ± SEM). (G) FACS analysis of ALDH activity in MOG35–55 pulsed dendritic cells from 45.1/Rag2–/– mice following 3 days in culture with CD45.2+CD4+ T cells from dLNs and mLNs of the indicated groups in conditions that block IL-4, GM-CSF, or both, or without treatment. Data are representative of 3 pairs of mice. Two-tailed Student’s t test was applied to determine significance in all cases.