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A Membrane Form of TNF- Presented by Exosomes Delays T Cell Activation-Induced Cell Death¹

Huang-Ge Zhang^2,*,, Cunren Liu^*, Kaihun Su^*, Shaohua Yu^*, Liming Zhang^*, Shuangqin Zhang^*, Jianhua Wang^*, Xu Cao, William Grizzle and Robert P. Kimberly^2,*

^* Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; Birmingham Veterans Administration Medical Center, Birmingham, AL 35233; and Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294

In common with many other cell types, synovial fibroblasts produce exosomes. In this study, we show that the exosomes produced by synovial fibroblasts obtained from individuals with rheumatoid arthritis (RASF), but not exosomes produced by synovial fibroblasts obtained from individuals with osteoarthritis, contain a membrane bound form of TNF- as demonstrated by colloidal gold immunostaining of TNF- and confirmed by both Western blot and mass spectrometry. The RASF-derived exosomes, but not exosomes derived from fibroblasts obtained from individuals with osteoarthritis, are cytotoxic for the L929 cell, a TNF--sensitive cell line, and stimulate activation of NF-B and induction of collagenase-1 in RASF. These effects are blocked by addition of soluble TNFR1 (sTNFbp), suggesting that a TNF--signaling pathway mediates these biological activities. sTNFbp also reduced the production of exosomes by RASF, suggesting the interruption of a positive amplification loop. Exosomes can transmit signals between cells, and RASF exosomes, effectively taken up by anti-CD3-activated T cells, activated AKT and NF-B and rendered these activated T cells resistant to apoptosis. Neutralization of exosomal membrane TNF- by sTNFbp partially reversed this resistance, suggesting that not only TNF- but also additional exosomal proteins may contribute to the development of apoptosis resistance.

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