Expression of membrane Hsp90 is a molecular signature of T cell activation

• Published in: Scientific reports 2022-10, Vol.12 (1), p.18091-18091, Article 18091
• Main Authors: Scarneo, Scott A., Smith, Aaron P., Favret, Jacob, O’Connell, Robert, Pickeral, Joy, Yang, Kelly W., Ferrari, Guido, Loiselle, David R., Hughes, Philip F., Kulkarni, Manjusha M., Gargesha, Madhusudhana, Scott, Bryan, Roy, Debashish, Haynes, Barton F., Kwiek, Jesse J., Haystead, Timothy A. J.
• Format: Article
• Language: English
• Subjects: 631/154/140; 631/154/309; 631/154/436; 631/154/53; 631/154/555; 631/154/556; Animal models; Animals; Arthritis, Rheumatoid - drug therapy; Autoimmune diseases; Cell activation; Disease Models, Animal; Heat shock proteins; HSP90 Heat-Shock Proteins - metabolism; Hsp90 protein; Humanities and Social Sciences; Humans; Immune clearance; Inflammatory bowel diseases; Localization; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Membrane trafficking; Metastases; Mice; multidisciplinary; Phenotypes; Rheumatoid arthritis; Science; Science (multidisciplinary); T cell receptors; T-Lymphocytes; Therapeutic applications; Therapeutic targets
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-22788-8

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 a membrane expressed form of Hsp90 (mHsp90) that previously appeared to be restricted to rapidly proliferating cells exhibiting a metastatic phenotype. Here, we used HS-131, a fluor-tethered mHsp90 inhibitor, to quantify the effect of T cell activation on the expression of mHsp90 in human and mouse T cells. In cell-based assays, stimulation of human T cells induced a 20-fold increase in mHsp90 expression at the plasma membrane, suggesting trafficking of mHsp90 is 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 reducing the mean clinical score in the CIA arthritis model. Our results suggest mHsp90 expression on T cells is a molecular marker of T cell activation and potentially a therapeutic target for chronic diseases such as rheumatoid arthritis.