EBI2 Is Highly Expressed in Multiple Sclerosis Lesions and Promotes Early CNS Migration of Encephalitogenic CD4 T Cells

Abstract

Arrival of encephalitogenic T cells at inflammatory foci represents a critical step in development of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. EBI2 and its ligand, 7α,25-OHC, direct immune cell localization in secondary lymphoid organs. CH25H and CYP7B1 hydroxylate cholesterol to 7α,25-OHC. During EAE, we found increased expression of CH25H by microglia and CYP7B1 by CNS-infiltrating immune cells elevating the ligand concentration in the CNS. Two critical pro-inflammatory cytokines, interleukin-23 (IL-23) and interleukin-1 beta (IL-1β), maintained expression of EBI2 in differentiating Th17 cells. In line with this, EBI2 enhanced early migration of encephalitogenic T cells into the CNS in a transfer EAE model. Nonetheless, EBI2 was dispensable in active EAE. Human Th17 cells do also express EBI2, and EBI2 expressing cells are abundant within multiple sclerosis (MS) white matter lesions. These findings implicate EBI2 as a mediator of CNS autoimmunity and describe mechanistically its contribution to the migration of autoreactive T cells into inflamed organs.

EBI2 in splenic and local immune responses and in autoimmunity

“…Furthermore, EBI2‐expressing cells are abundant in MS lesions, and EBI2 positive T cells have been found in the inflamed white matter. In addition, analysis of different human T cell subsets revealed that human Th17 cells are almost completely EBI2 positive and express high levels of this protein compared to other T cell subsets . Functionally, human Th cells migrate toward 7α,25‐OHC in an EBI2‐dependent manner similar to murine Th cells …”

“…Though, no difference in EAE onset and severity could be observed in mice lacking EBI2. However, using a transfer model of the disease, in which encephalitogenic T cells were transferred to other naïve mice, a robust delay of disease onset was observed using T cells lacking EBI2 (Fig. ).…”

“…An assessment of the expression of the EBI2 ligand‐generating enzyme CH25H in microglia showed that microglia from naïve mice do not express CH25H but that in the inflamed CNS, expression of this enzyme was dramatically induced (Fig. ).…”

“…Among these so‐called encephalitogenic T cells, Th17 cells expressing IL‐17 have been shown to play a crucial role for the pathogenesis of the disease . Interestingly, changes in oxysterol levels have been detected in the CNS of EAE animals as well as in MS patients (Fig. ).…”

Single-cell profiling reveals GPCR heterogeneity and functional patterning during neuroinflammation

“…, EBI2-FL-EGFP (63), and EBI2-FL-EGFP 2D2 mice were bred at the Institute for Molecular Medicine at the University Medical Center of the Johannes Gutenberg-University Mainz. All mouse lines were on a pure C57BL/6 background.…”