The heat-stable antigen determines pathogenicity of self-reactive T cells in experimental autoimmune encephalomyelitis
Xue-Feng Bai, … , Pan Zheng, Yang Liu
Xue-Feng Bai, … , Pan Zheng, Yang Liu
Published May 1, 2000
Citation Information: J Clin Invest. 2000;105(9):1227-1232. https://doi.org/10.1172/JCI9012.
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Article

The heat-stable antigen determines pathogenicity of self-reactive T cells in experimental autoimmune encephalomyelitis

Abstract

Induction of myelin-specific CD4 T cells is a pivotal event in the development of experimental autoimmune encephalomyelitis (EAE). Other checkpoints in EAE pathogenesis have not been clearly defined, although multiple genetic loci are known to influence EAE development. We report here that targeted mutation of the heat-stable antigen (HSA) abrogates development of EAE despite a complete lack of effect on induction of autoimmune T cells. To test whether T-cell expression of HSA is sufficient, we created transgenic mice in which HSA is expressed exclusively in the T-cell lineage. We found that these mice remain resistant to EAE induction. Adoptive transfer studies demonstrate that both T cells and non–T cells must express HSA in order for the pathogenic T cells to execute their effector function. Moreover, HSAIg, a fusion protein consisting of the extracellular domain of the HSA and the Fc portion of immunoglobulin, drastically ameliorates the clinical sign of EAE even when administrated after self-reactive T cells had been expanded. Thus, identification of HSA as a novel checkpoint, even after activation and expansion of self-reactive T cells, provides a novel approach for immunotherapy of autoimmune neurologic diseases, such as multiple sclerosis.

Authors

Xue-Feng Bai, Jin-Qing Liu, Xingluo Liu, Yong Guo, Karen Cox, Jing Wen, Pan Zheng, Yang Liu

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Targeted mutations of HSA and CD28 reveal two distinct checkpoints in th...
Targeted mutations of HSA and CD28 reveal two distinct checkpoints in the development of EAE. (a) Targeted mutations of either HSA or CD28 prevent induction of EAE. WT, CD28–/–, or HSA–/– mice were immunized with MOG peptide. Clinical signs were scored as described in Methods. (b) Proliferative response of lymph node T cells to MOG peptides. Draining lymph node cells from day 10–immunized mice were stimulated with given concentrations of MOG peptide and irradiated syngeneic naive spleen cells as antigen-presenting cells. (c) Enumeration of cytokine-producers by ELISpot. Draining lymph node cells used in b were used as responder cells. The numbers of cells secreting either IL2, IL4, or IFN-γ among 1 × 106 lymph node cells in response to MOG peptide (AA35-55) are presented. Data shown are means ± SEM from three independent experiments.