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Expression of extracellular Hsp90 is a molecular signature of T cell activation, providing a means to image and target T Cell activation in autoimmune disease

By Scott Scarneo, Aaron Smith, Jacob Favret, Robert O'connell, Joy Pickeral, Kelly Yang, Guido Ferrari, David Loiselle, Philip Hughes, Manjusha Kulkarni, Madhusudhana Gargesha, Bryan Scott, Debashish Roy, Barton Haynes, Jesse Kweik, Timothy Haystead

Posted 07 Jun 2021
bioRxiv DOI: 10.1101/2021.06.06.446823

Heat shock protein 90 (Hsp90) maintains cellular proteostasis during stress and has been under investigation as a therapeutic target in cancer for over two decades. We and others have identified an extracellularly expressed form of Hsp90, eHsp90, that previously appeared to be restricted to rapidly proliferating cells exhibiting a metastatic phenotype. Here, we used HS-131, a fluor-tethered eHsp90 inhibitor, to quantify the effect of T cell activation on the expression of eHsp90 in human and mouse T cells. In cell based assays, stimulation of human T cells induced a 20-fold increase in eHsp90 expression at the plasma membrane, suggesting trafficking of eHsp90 is acutely regulated by TCR and inflammatory mediated signaling. Following injection of HS-131 in mouse models of human rheumatoid arthritis and inflammatory bowel disease, we detected localization of the probe at sites of active disease, consistent with immune cell invasion. Moreover, despite rapid hepatobiliary clearance, HS-131 demonstrated efficacy in delaying the onset and progression of disease in the arthritis model. Our results suggest eHsp90 expression at the plasma membrane of T cells is a molecular marker of autoimmune induced activation and potentially a therapeutic target for chronic diseases such as rheumatoid arthritis and inflammatory bowel disease.

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