The receptor for advanced glycation end products (RAGE) affects T cell differentiation in OVA induced asthma.

Eitan M Akirav,Paula Preston-Hurlburt,Kevan C Herold,Raphael Clynes,Ann Marie Schmidt,Octavian Henegariu,Muriel Moser

doi:10.1371/journal.pone.0095678

Eitan M Akirav, Paula Preston-Hurlburt + Show 5 more

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https://doi.org/10.1371/journal.pone.0095678

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Abstract

The receptor for glycation end products (RAGE) has been previously implicated in shaping the adaptive immune response. RAGE is expressed in T cells after activation and constitutively in T cells from patients with diabetes. The effects of RAGE on adaptive immune responses are not clear: Previous reports show that RAGE blockade affects Th1 responses. To clarify the role of RAGE in adaptive immune responses and the mechanisms of its effects, we examined whether RAGE plays a role in T cell activation in a Th2 response involving ovalbumin (OVA)-induced asthma in mice. WT and RAGE deficient wild-type and OT-II mice, expressing a T cell receptor specific for OVA, were immunized intranasally with OVA. Lung cellular infiltration and T cell responses were analyzed by immunostaining, FACS, and multiplex bead analyses for cytokines. RAGE deficient mice showed reduced cellular infiltration in the bronchial alveolar lavage fluid and impaired T cell activation in the mediastinal lymph nodes when compared with WT mice. In addition, RAGE deficiency resulted in reduced OT-II T cell infiltration of the lung and impaired IFNγ and IL-5 production when compared with WT mice and reduced infiltration when transferred into WT hosts. When cultured under conditions favoring the differentiation of T cells subsets, RAGE deficient T cells showed reduced production of IFNγ but increased production of IL-17. Our data show a stimulatory role for RAGE in T activation in OVA-induced asthma. This role is largely mediated by the effects of RAGE on T cell proliferation and differentiation. These findings suggest that RAGE may play a regulatory role in T cell responses following immune activation.

Highlights

Tcell activation is determined by intrinsic cellular factors consisting of T cell receptor signaling and costimulatory signals
We examined whether Receptor for Advanced Glycation End Products (RAGE) deficiency affects overall immune activation and cellular infiltration in mice immunized with intranasal-OVA
Hematoxylin and eosin staining of lung sections from WT or RAGE2/2 revealed an accumulation of mononuclear cell in the lungs and airways of WT mice that was reduced in the lungs of RAGE2/2 mice (Figure 1A)

Summary

Introduction

Tcell activation is determined by intrinsic cellular factors consisting of T cell receptor signaling (signal 1) and costimulatory signals (signal 2). Blockade of RAGE activation with soluble RAGE attenuated the adoptive transfer of diabetes in NOD mice and reduced recurrent diabetes in syngeneic islet grafts and islet allograft rejection [1]. This reduction in diabetes was correlated with reduced cellular infiltration of the islet and increased expression of anti-inflammatory cytokines such as IL-10 and TGF-b [1]. In transgenic mice expressing a T cell receptor specific for ovalbumin (OVA) (OT-II), the transfer of RAGE-deficient OT-II T cells into RAGE-sufficient hosts resulted in reduced proliferative responses following OVA immunization. This effect was attributable to the expression of RAGE on the OT-II T cells [2]

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