Diverting T helper cell trafficking through increased plasticity attenuates autoimmune encephalomyelitis
Danielle Califano, Keith J. Sweeney, Hung Le, Jeffrey VanValkenburgh, Eric Yager, William O’Connor Jr., Jeffrey S. Kennedy, David M. Jones, Dorina Avram
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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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 1

CD4+ T cells of Bcl11bF/F/dLck-iCre mice upregulate GATA3 and IL-4, but do not lose expression of Rorγt, IL-17, or GM-CSF during EAE.

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CD4+ T cells of Bcl11bF/F/dLck-iCre mice upregulate GATA3 and IL-4, but ...
(A) GATA3 and Rorγt levels evaluated by FACS analysis in naive CD4+ T cells from LNs of the indicated groups of mice. Gray shaded area indicates negative control. (B) Average frequency of naive CD4+ T cells that express GATA3 in the indicated groups. *P ≤ 0.05, n = 5 (mean ± SEM). (C) FACS analysis of GATA3 and Rorγt levels in CD4+ T cells in the dLNs and mLNs of the indicated groups on day 12 following EAE induction. (D) Average frequency of GATA3+ (left) or GATA3+Rorγt+ (right) CD4+ T cells in the indicated groups. *P ≤ 0.05, n = 5 (mean ± SEM). (E) FACS analysis of frequencies of IL-17– and GM-CSF–producing CD4+ T cells from dLNs and mLNs of the indicated groups on day 12 after EAE induction. (F) Average frequency of IL-17+GM-CSF+CD4+ T cells in the indicated EAE groups. *P ≤ 0.05; NS indicates P > 0.05, n = 5 (mean ± SEM). (G) FACS analysis of frequencies of IL-4– and IL-17–producing CD4+ T cells from dLNs and mLNs of the indicated groups on day 12 after EAE induction. (H) Average frequencies of IL-4+CD4+ T cells (left) and IL-4+IL-17+CD4+ T cells in the indicated groups *P ≤ 0.05, n = 5 (mean ± SEM). Two-tailed Student’s t test was applied to determine significance.