Intercellular Adhesion Molecule-1 (ICAM-1) and ICAM-2 Differentially Contribute to Peripheral Activation and CNS Entry of Autoaggressive Th1 and Th17 Cells in Experimental Autoimmune Encephalomyelitis.

Neda Haghayegh Jahromi,Federica Moalli,Donovan Duc,Elisa Kaba,Urban Deutsch,Luca Marchetti,Heidi Tardent,Jens V Stein,Camilla Basso,Federica Sallusto,Britta Engelhardt,Caroline Pot

doi:10.3389/fimmu.2019.03056

Abstract

In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), myelin-specific T cells are activated in the periphery and differentiate in T helper (Th) 1 and Th17 effector cells, which cross the blood-brain barrier (BBB) to reach the central nervous system (CNS), where they induce neuroinflammation. Here, we explored the role of intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 in the activation of naïve myelin-specific T cells and in the subsequent migration of differentiated encephalitogenic Th1 and Th17 cells across the BBB in vitro and in vivo. While on antigen-presenting cells ICAM-1, but not ICAM-2 was required for the activation of naïve CD4+ T cells, endothelial ICAM-1 and ICAM-2 mediated both Th1 and Th17 cell migration across the BBB. ICAM-1/-2-deficient mice developed ameliorated typical and atypical EAE transferred by encephalitogenic Th1 and Th17 cells, respectively. Our study underscores important yet cell-specific contributions for ICAM-1 and ICAM-2 in EAE pathogenesis.

Highlights

Multiple sclerosis (MS) is considered an autoimmune inflammatory demyelinating disease of the central nervous system (CNS)
To explore the role of intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 on DCs in activating myelin-specific T cells, we first asked if MOGaa35−55 pulsed DCs lacking ICAM-1 and ICAM-2 display visible differences in their dynamic interactions with naïve CD4+ T cells compared to WT DCs in peripheral LNs
Side-by-side comparison of the dynamic interactions of 2D2 T cells with WT or ICAM-1/-2−/− DCs using two-photon intravital microscopy (2P-IVM) of popliteal LNs [42, 43], showed that 2D2-GFP CD4+ T cells preferentially interacted with WT rather than ICAM-1/-2−/− DCs (Figures 1A,B; Supplementary Video 1)

Summary

Introduction

Multiple sclerosis (MS) is considered an autoimmune inflammatory demyelinating disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE), a prototypic animal model for MS, mimics many aspects of the acute inflammatory phase of the human disease [1]. In EAE, naïve myelin-reactive CD4+ T cells are activated and differentiated in peripheral lymphoid tissue into encephalitogenic Th1 or Th17 cells, which travel in the blood circulation to the CNS. After crossing the blood-brain barrier (BBB) they infiltrate in the CNS parenchyma, leading to clinical manifestation of the disease [2]. EAE can be actively induced by immunization with CNS myelin antigens emulsified in complete Freund’s adjuvant (aEAE) or by injection of myelin-reactive CD4+ T cells into syngeneic naïve recipients (tEAE) [3, 4]

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Results

Conclusion