B7-H3 Promotes Pathogenesis of Autoimmune Disease and Inflammation by Regulating the Activity of Different T Cell Subsets.

Liqun Luo,Sheng Yao,Gang Zhou,Haiying Xu,Koji Tamada,Zhou Zhu,Jan M A Van Deursen,Lieping Chen,William Ruff,Andrew D Flies,Megan Broadwater,Yuwen Zhu,Gefeng Zhu,Ignacio Melero,Lanqing Huang

doi:10.1371/journal.pone.0130126

Abstract

B7-H3 is a cell surface molecule in the immunoglobulin superfamily that is frequently upregulated in response to autoantigens and pathogens during host T cell immune responses. However, B7-H3's role in the differential regulation of T cell subsets remains largely unknown. Therefore, we constructed a new B7-H3 deficient mouse strain (B7-H3 KO) and evaluated the functions of B7-H3 in the regulation of Th1, Th2, and Th17 subsets in experimental autoimmune encephalomyelitis (EAE), experimental asthma, and collagen-induced arthritis (CIA); these mouse models were used to predict human immune responses in multiple sclerosis, asthma, and rheumatoid arthritis, respectively. Here, we demonstrate that B7-H3 KO mice have significantly less inflammation, decreased pathogenesis, and limited disease progression in both EAE and CIA mouse models when compared with littermates; these results were accompanied by a decrease in IFN-γ and IL-17 production. In sharp contrast, B7-H3 KO mice developed severe ovalbumin (OVA)-induced asthma with characteristic infiltrations of eosinophils in the lung, increased IL-5 and IL-13 in lavage fluid, and elevated IgE anti-OVA antibodies in the blood. Our results suggest B7-H3 has a costimulatory function on Th1/Th17 but a coinhibitory function on Th2 responses. Our studies reveal that B7-H3 could affect different T cell subsets which have important implications for regulating pathogenesis and disease progression in human autoimmune disease.

Highlights

Upon T cell receptor-mediated recognition of MHC antigenic peptides, T cell responses to antigens, including autoreactive antigens, are orchestrated by a group of cell surface signaling molecules
A lack of B7-H3 ameliorated the effects of EAE and significantly decreased symptoms of collagen-induced arthritis (CIA), which were accompanied by a decrease in Th1- and/ or Th17-type cytokine responses to autoantigens
Our findings reveal a dichotomy for B7-H3's role in the regulation of T cell subsets, and provide important clues that will assist in designing new immune modulations that target this pathway and treat disease

Summary

Introduction

Upon T cell receptor-mediated recognition of MHC antigenic peptides, T cell responses to antigens, including autoreactive antigens, are orchestrated by a group of cell surface signaling molecules. The role of endogenous B7-H3 in the pathogenesis and progression of autoimmune disease has been evaluated by various laboratories using both monoclonal antibodies (mAb) and B7-H3 deficient mice (KO), but the results are somewhat contradictory with both costimulatory and coinhibitory effects being described in various model systems [8,9]. One interpretation for these contradicting results is that B7-H3 plays a differential role in the regulation of distinct T cell subsets. To delineate the role of B7-H3 in the differential regulation of T cell subsets, we constructed a B7-H3-deficient mouse strain and studied the differential roles of B7-H3 in these T cell subsets and in multiple mouse models where pathogenic T cells are biased toward specific T cell subsets

Methods

Results

Conclusion