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

Abstract

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-α as demonstrated by colloidal gold immunostaining of TNF-α 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-α-sensitive cell line, and stimulate activation of NF-κB and induction of collagenase-1 in RASF. These effects are blocked by addition of soluble TNFR1 (sTNFbp), suggesting that a TNF-α-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-κB and rendered these activated T cells resistant to apoptosis. Neutralization of exosomal membrane TNF-α by sTNFbp partially reversed this resistance, suggesting that not only TNF-α but also additional exosomal proteins may contribute to the development of apoptosis resistance.

Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF‐α mediated NF‐κB pathway

“…We found an elevated expression of TNF‐α in mature DC‐exos and they were mainly expressed on exosomal membrane. This finding was consistent with previous studies 8, 24. We then down‐regulated TNF‐α in DC‐exos and observed that the expression of adhesion molecules by HUVECs were attenuated, indicating a direct interaction between DC‐exos and HUVECs by TNF‐α.…”

Soluble TNF‐α but not transmembrane TNF‐α sensitizes T cells for enhanced activation‐induced cell death

“…These observations nicely fit with our earlier finding that the exclusive presence of TNF as a 26 kDa non-cleavable mutant accelerates colonic inflammation in a T-cell transfer model of colitis [23]. Lack of sensitization of primed T cells for AICD in the absence of sTNF may even be potentiated by tmTNF mediated delay of AICD [24]. However, in our experiments, no additional tmTNFmediated anti-apoptotic effect was found as tmTNF and TNF À/À CD4 1 T cells were equally resistant to AICD (Fig.…”

Engineered CD8+ cytotoxic T cells with fiber-modified adenovirus-mediated TNF-α gene transfection counteract immunosuppressive interleukin-10-secreting lung metastasis and solid tumors

“…Our data showed that the number of detected OVA-specific CD8 þ T cells in peripheral blood of C57BL/6 mice with CD8 þ T(TNFa À/À )-cell transfer or in peripheral blood of C57BL/ 6(TNF-a À/À ) mice with CD8 þ T-cell transfer all dramatically dropped to 0.5 and 0.2% of the total CD8 þ T-cell population and both completely disappeared at days 12 and 30 after transfer, respectively, indicating that both the donor's cellular and the host TNF-a are important in CD8 þ T-cell survival in vivo. Recently, it has been reported that membrane TNF-a can delay T-cell activation-induced cell death by activation of AKT and NF-kB, 64 which leads to elongated T-cell survival. Our results are thus consistent with a previous report by Dobrazanski, et al, 65 demonstrating that CD8 þ T-cell therapeutic effect was significantly less efficient in TNF-a À/À KO mice.…”